BACKGROUND OF THE INVENTION The importance of potassium channels was first recognized approximately fifty years ago when Hodgkin and Huxley discovered that potassium ions contributed to the current that excited the squid giant axon. Research in the area, however, was hampered by the lack of selective, high affinity ligands for potassium channels. But the advent of recombinant DNA techniques and single cell and whole cell voltage clamp techniques has changed the slow pace of the field. Indeed, potassium channels that exhibit functional, pharmacological and tissue distribution characteristics have been cloned. These cloned potassim channels are useful targets in assays for identifying candidate compounds for the treatment of various disease states.

Potassium channels have turned out to be the most diverse family of ion channels discovered to date. They modulate a number of cellular events such as muscle contraction, neuro-endocrine secretion, frequency and duration of action potentials, electrolyte homeostatis, and resting membrane potential.

Potassium channels are expressed in eukaryotic and procaryotic cells and are elements in the control of electrical and non-electrical cellular functions. Potassium channels have been classified according to their biophysical and pharmacological characteristics. Subclasses of these channels have been named based on amino acid sequence and functional properties. Salient among these are the voltage dependent potassium channels, for example voltage gated potassium channels (e. g., K, Ky2, Kv3, Kr4). Subtypes within these subclasses have been characterized as to their

putative function, pharmacology and distribution in cells and tissues (Chandy and Gutman, "Voltage-gated potassium channel genes"in Handbook of Receptors and Channels-Ligand and Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al. , Curr. Opin. Neurobiol. 5: 268,1995). For example, the Kvl class of potassium channels is further subdivided depending on the molecular sequence of the channel, for example Kvl. l, Kvl. 2, Kvl. 3, Kvl. 4, Kvl. 5, Kvl. 6, and Kvl. 7. Functional voltage- gated K+ channels can exist as multimeric structures formed by the association of either identical or dissimilar subunits. This phenomena is thought to account for the wide diversity of K+ channels. However, subunit compositions of native K+ channels and the physiologic role that particular channels play are, in most cases, still unclear.

Membrane depolarization by K, 1. 3 inhibition has been shown to be an effective method to prevent T-cell proliferation and therefore has applications in many autoimmune conditions. Inhibition of K+ channels in the plasma membrane of human T-lymphocytes has been postulated to play a role in eliciting immunosuppressive responses by regulating intracellular Ca++ homeostasis, which has been found to be important in T-cell activation.

The Kvl. 3 voltage-gated potassium channel is found in neurons, blood cells, osteoclasts and T-lymphocytes. The Chandy and Cahalan laboratories proposed a hypothesis that blocking the Kvl. 3 channel would elicit an immunosuppressant response. (Chandy et al. , J. Exp. Med. 160,369, 1984; Decoursey et al., Nature, 307, 465,1984). However, the K+ channel blockers employed in their studies were non- selective. Until research with the peptide margatoxin, a peptide found in scorpion venom, no specific inhibitor of the Kvl. 3 channel existed to test this hypothesis.

Although a laboratory (Price et al. , Proc. Natl, Acad, Sci. USA, 86,10171, 1989) showed that charybdotoxin would block Kvl. 3 in human T-cells, charybdotoxin was subsequently shown to inhibit four different K+ channels (Kv1. 3 and three distinct small conductance Ca++ activated K+ channels) in human T-lymphocytes, limiting the use of this toxin as a probe for the physiological role of Kyl. 3 (Leonard et al. , Proc.

Natl, Acad. Sci, USA, 89,10094, 1992). Margatoxin, on the other hand, blocks only Kvl. 3 in T-cells, and has immunosuppressant activity on both in in vitro and in vivo models. (Lin et al. , J. exp. Med, 177,637, 1993). The therapeutic utility of this compound, however, is limited by its potent toxicity. Recently, a class of compounds

has been reported that may be an attractive alternative to the above mentioned drugs, see for example U. S. Patent Nos. 5,670, 504; 5,631, 282; 5,696, 156; 5,679, 705; and 5, 696,156. While addressing some of the activity/toxicity problems of previous drugs, these compounds tend to be of large molecular weight and are generally produced by synthetic manipulation of a natural product, isolation of which is cumbersome and labor intensive.

Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and It diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves ophthalmopathy and asthma.

Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of auto-antibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.

One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAID's act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.

Cyclosporin A (CsA), which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs. In 1993, FK-506 (Prograf) was approved by the US FDA for the prevention of rejection in liver transplantation. CsA and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's

foreign protein. In 1994, CsA was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis. Though they are effective in fighting transplant rejection, CsA and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, a selective immunosuppressant without these side effects still remains to be developed.

Potassium channel inhibitors promise to be the solution to this problem.

Atrial fibrillation (AF) and atrial flutter are the most common cardiac arrhythmias in clinical practice and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class in antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.

Antiarrhythmic agents of Class HI are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression.

Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class m properties (Singh B. N., Vaughan Williams E. M. "A Third Class of Anti-Arrhythmic Action: Effects On Atrial And Ventricular Intracellular Potentials And Other Pharmacological Actions On Cardiac Muscle, of MJ 1999 and AH 3747"Br. J. Pharmacol 1970; 39: 675-689. and Singh B. N. , Vaughan Williams E. M, "The Effect of Amiodarone, A New Anti- Anginal Drug, On Cardiac Muscle", Br J. Pharmacol 1970; 39: 657-667), but these are not selective Class m agents. Sotalol also possesses Class II effects which may cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone, also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects (Nademanee, K.

"The Amiodarone Odessey". J. Am. Coll. Cardiol. 1992; 20: 1063-1065. ) Drugs of

this class are expected to be effective in preventing ventricular fibrillation. Selective class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.

Class in agents increase myocardial refractoriness via a prolongation of cardiac action potential duration. Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i. e. Na+ or Ca2+ currents ; hereinafter INa and ICa, respectively) or by reducing outward repolarizing potassium (K+) currents. The delayed rectifier (IK) K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (Ito) and inward rectifier (IKI) K+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively.

Cellular electrophysiologic studies have demonstrated that IK consists of two pharmacologically and kinetically distinct K+ current subtypes, IKr (rapidly activating and deactivating) and Ins (slowly activating and deactivating) (Sanguinetti and Jurkiewicz, Two Components Of Cardiac Delayed Rectifier K+ Current: Differential Sensitivity To Block By Class in Antiarrhythmic Agents, J Gen Physiol 1990, 96: 195-215). Class nI antiarrhythmic agents currently in development, including d- sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide-N- [1'-6-cyano-1, 2,3, 4-tetrahydro-2-naphthalenyl) -3,4-dihydro- 4-hydroxyspiro [2H-1-benzopyran-2, 4'-piperidin]-6yl] monochloride, predominantly, if not exclusively, block Ihr. Although, amiodarone is a blocker of Ins (Balser J. R.

Bennett, P. B. , Hondeghem, L. M. and Roden, D. M. "Suppression Of Time-Dependent Outward Current In Guinea Pig Ventricular Myocytes: Actions Of Quinidine And Amiodarone. Circ. Res. 1991,69 : 519-529), it also blocks INa and lea, effects thyroid function, is as a nonspecific adrenergic blocker, and acts as an inhibitor of the enzyme phospholipase (Nademanee, K. "The Amiodarone Odessey". J. Am. Coll.

Cardiol. 1992; 20: 1063-1065). Therefore its method of treating arrhythmia is uncertain. Most Class HE agents that are known to be in development predominantly block IE2- Reentrant excitation (reentry) has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man. Reentrant excitation requires a

critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF. Increasing myocardial refractoriness by prolonging action potential duration (APD), prevents and/or terminates reentrant arrhythmias. Most selective Class III antiarrhythmic agents currently in development, such as d-sotalol and dofetilide predominantly, if not exclusively, block Ikr, the rapidly activating component of IK found both in the human atrium and ventricle.

Since these Ikr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsades de points has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class m Antiarrhythmic Drug Therapy", Am J. Cardiol, 1993; 72: 44B-49B). This exaggerated effect at slow heart rates has been termed "reverse frequency-dependence", and is in contrast to frequency-independent or frequency-dependent actions (Hondeghem, L. M. "Development of Class in Antiarrhythmic Agents". J. Cadiovasc. Cardiol. 20 (Suppl. 2): S17-S22).

The slowly activating component of the delayed rectifier (Iks) potentially overcomes some of the limitations of Ikr blockers associated with ventricular arrhythmias. Because of its slow activation kinetics however, the role of Iks in atrial repolarization may be limited due to the relatively short APD of the atrium.

Consequently, although Iks blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect SVT is considered to be minimal.

The ultra-rapidly activating delayed rectifier K+ current (Ikur) is believed to represent the native counterpart to a cloned potassium channel designated Kvl. 5 and, while present in human atrium, it appears to be absent in human ventricle.

Furthermore, because of its rapidity of activation and limited slow inactivation, Ikur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of Ikur, that is a compound which blocks Kvl. 5, would overcome the short coming of other compounds by prolonging refractoriness by retarding repolarization in the human atrium without causing the delays in ventricular

reporlarization that underlie arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class m drugs.

In intact human atrial myocytes an ultra-rapidly activating delayed rectifier K+ current Ikur which is also known as the sustained outward current, Lu, or Iso, has been identified and this current has properties and kinetics identical to those expressed by the human K+ channel clone (hKvl. 5, HK2) when isolated from human heart and stably expressed in human (HEK-293) cell lines (Wang et al. , 1993, Circ Res 73: 1061-1076; Fedida et al. , 1993, Circ Res 73: 210-216; Snyders et al. , 1993, J Gen Physiol 101: 513-543) and originally cloned from rat brain (Swanson et al. , 10, Neuron 4: 929-939). Although various antiarrythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, antiarrythmic agents of Class I according to the classification scheme of Vaughan-Williams ("Classification Of Antiarrhythmic Drugs: In: Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp449-472,1981) which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.

SUMMARY OF THE INVENTION The present invention provides heterocylyl compounds of the following formula I, including enantiomers, diastereomers, and salts thereof, useful as inhibitors of potassium channel function (especially inhibitors of the Kvl subfamily of voltage gated K+ channels, more especially inhibitors of Kvl. 5 which has been linked to the ultra-rapidly activating delayed rectifier K+ current, IKur) for the treatment of disorders such as arrhythmia and IKur-associated disorders:

including enantiomers, diastereomers and salts thereof wherein m and p are independently 0,1, 2 or 3 provided that the sum of m and p is at least 2; Q is NR', O, S, S (O) or S (O) 2 ; R1 is -C(=NR8b)R8c, -SO2R8c, -OC(O)CCl3, -C (=S) R8C, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, perfluoroalkyl, cyano, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally subsituted alkenyl, or optionally subsituted alkynyl; R2 is heteroaryl, (heteroaryl) alkyl, aryl, (aryl) alkyl, heterocyclo, (heterocyclo) alkyl, alkyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T1, T or T3 ; J is a bond, C1-4 alkylene optionally independently substituted with one or more groups Tla, T2a or T3a, or C1-4 alkenylene optionally independently substituted with one or more groups Tla, T2a or T3a ; R3 is

R4 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl) alkyl or heteroaryl any of which may be optionally independently substituted with one or more groups Tlb, T2b or T3b ; R5 is a) NR6aR7a cyano or (b) heteroaryl, (heteroaryl) alkyl, aryl, (aryl) alkyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo, (heterocyclo) alkyl, or alkyl any of which may be optionally independently substituted with one or more groups Tlc, T2c or T3C ; R6 R6a, R7, R7a, R8, R8a, R8a1, R8a2, and R8a3 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy) alkyl, (alkoxy) alkyl, (aryloxy) alkyl, (heterocyclooxy) alkyl, (heteroaryloxy) alkyl, (cyano) alkyl, (alkenyl) alkyl, (alkynyl) alkyl, cycloalkyl, (cycloalkyl) alkyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, heterocyclo, (heterocyclo) alkyl,-C (O) R9,

-CO2R9, -C(O)-NR9R10, or -NR9R10 any of which may be optionally independently substituted with one or more groups Tld, T2d or T3d ; or R6 and R7, or R6a and R7a together with the nitrogen atom to which they are attached may combine to form a 4 to 8 membered heterocyclo ring optionally independently substituted with one or more groups Tld, T2d or T3d ; or one of R6 or R7, may combine with one of R8, R8a or R9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T or T or one of R6a or R7a, may combine with R8al to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T1d, T2d or T3d R is H, alkyl, aryl, cyano, nitro, acyl or-SO2 (alkyl) were the alkyl and aryl groups may be optionally independently substituted with one or more groups Tld, T2d or T3d ; R8C is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocylco, heteroaryl, alkoxy or aryloxy any of which may be optionally independently substituted with one or more groups T1d, T2d or T3d ; R8d is R4, COR4, CO2R4, SO2R4, CONR6R7, or SO2NR6R7; R9 and Rl° are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy) alkyl, (alkoxy) alkyl, (aryloxy) alkyl, (heterocylooxy) alkyl, (heteroaryloxy) alkyl, cycloalkyl, (cycloalkyl) alkyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, heterocyclo, or (heterocyclo) alkyl any of which may be optionally independently substituted with one or more groups T1f, T2f or T3f or R9 and Rlo together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups Tlf, Tuf or T3f ; W is =NR8a1 =N-CO2R8a1, =N-COR8a1, =N-CN, =N-SO2R8a1, or X1 is O, S, NR8a2 or CH2 ; Z, Z1 and Z2 are independently =O, =S, =NR8a3 or =N-CN ;

Rx is one or more optional substituents, attached to any available ring carbon atom, independently selected from Tlg, T2g or T3g ; Tl-lg, T2-2g, and T3-3g are are each independently (1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl, (aryl) alkyl, heterocyclo, (heterocylco) alkyl, heteroaryl, or (heteroaryl) alkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Tl-lg T2-2g and T3-3g, (2) -OH or-OT6, (3) -SH or -ST6, (4)-C (O) tH,-C (O) tT6, or-O-C (O) T6, where t is 1 or 2; (5) -SO3H, -S(O)tT6, or S (O) tN (T9)T6, (6) halo, (7) cyano, (8) nitro, (9) -T4-NT7T8, (10) -T4-N(T9)-T5-NT7T8, (11) -T4-N(T10)-T5-T6, (12) -T4-N(T10)-T5-H, (13) oxo, T4 and T5 are each independently (1) a single bond, (2) -T11-S (O) c-T12- (3) -T11-C (O)-T-, (4) -T11-C(S)-T12, (5) -T11-O-T12-, (6) -T11-S-T12-,

(7) -T11-O-C(O)-T12-, (8) -T11-C(O)-O-T12-, (9) -T11-C(=NT9a)-T12-, or (10) -T11-C (o)-c (O)-T12- T7, T, T9, T and T (1) are each independently hydrogen or a group provided in the definition of <BR> <BR> <BR> 6<BR> <BR> T@, or (2) T7 and T8 may together be alkylene or alkenylene, completing a 3-to 8- membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of Tl-lg, T2-2g and T3-3g, or (3) T7 or T, together with T9, may be alkylene or alkenylene completing a 3-to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of Tl-lg, T2- 2g and T3-3g, or (4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group -N=CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6 ; and Tll and Tl2 are each independently (1) a single bond, (2) alkylene, (3) alkenylene, or (4) alkynylene.

The present invention provides novel methods for the prevention and treatment of arrhythmia and IKur-associated disorders employing one or more compounds of the formula I, enantiomers, diastereomers or pharmaceutically acceptable salts thereof. In particular the present invention provides a novel method for the selective prevention and treatment of supraventricular arrhythmias.

Preferred compounds within the scope of formula I include compounds and salts thereof wherein one or more, and especially all of Q, R2, J and R3 are selected from the following definitions: Q is NRl or O ;

R'is -C (=S) R8C,-C (=NR8b)R8c or heteroaryl; R is aryl, (aryl) alkyl or heteroaryl any of which may be optionally independently substituted with one or more T, T2T3 ; J is a bond or methylene; and R3 is More preferred compounds within the scope of formula I include compounds and salts thereof wherein one or more, and especially all of Q, R2, J and R3 are selected from the following definitions: Q is NRI ; R1 is -C(=S)R8c, or heteroaryl; R2 is aryl, (aryl) alkyl or heteroaryl (especially where aryl is phenyl and heteroaryl is thiophenyl) any of which may be optionally independently substituted with one or more T1, T2 T3 ; J is a bond or methylene; R3 is

R4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl) alkyl, heteroaryl or (heteroaryl) alkyl any of which may be optionally independently substituted with one or more Tlb, T T3b ; R5 is (a)-NR6aR7a or (b) aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, heterocyclo or (heterocyclo) alkyl any of which may be optionally independently substituted with one or more T1c, T2c T3C ; R6, R6a, R7 and R7a are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl) alkyl, (alkoxy) alkyl, cycloalkyl, (cycloalkyl) alkyl, (hydroxy) alkyl, heteroaryl, (heteroaryl) alkyl, heterocyclo, (heterocyclo) alkyl, (aryloxy) alkyl,-C (O) R9, - C02R9, or-C (O)-NR9R10 any of which may be optionally independently substituted with one or more Tld, T T3d ; or R6 and R7, or R6a and R7a together with the nitrogen atom to which they are attached combine to form an optionally substituted 4 to 8 membered heterocyclo ring (e. g., R8a is H, alkyl, or (aryl) alkyl; R8c is (a) alkyl, aryl, heteroaryl any of which may be optionally independently substituted with one or more Tld, T2d T3d ; or (b)-NR9R10 ;

W is =N-CN; Z1 is =O or =N-CN ; and T, T1b, T1c, T1d, T2, T2b, T2c, T2d, T3, T3b, T3c and T3d are independently halo, cyano, alkyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, haloalkyl,-OH,-OT6, -C(O)tT6, -SO2T6, -T4NT7T8, or -T4N(T10)T5-T6.

Preferred compounds generally have the structure Preferred-JR3 moities include: DETAILED DESCRIPTION OF THE INVENTION The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout

the present specification, individually or as part of another group, unless otherwise indicated.

The terms"alk"or"alkyl"refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc.

Lower alkyl groups, that is, alkyl groups of 1 to 6 carbon atoms, are generally most preferred. The term"substituted alkyl"refers to alkyl groups substituted with one or more groups listed in the definition of Tl-lg, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, -OT6, -C(O)tT6, -OC(O)T6, -T4-NT7T8, -T4-N (T9)-T5-T6,-S (O) tT6 or-S (O) tN (T9)T6.

The term"alkenyl"refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one double carbon to carbon bond (either cis or trans), such as ethenyl. The term"substituted alkenyl"refers to alkenyl groups substituted with one or more groups listed in the definition of Tl-lg, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, -OT6, -C(O)tT6, -OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, -S(O)tT6 or -S(O)tN(T9)T6.

The term"alkynyl"refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one triple carbon to carbon bond, such as ethynyl. The term"substituted alkynyl"refers to alkynyl groups substituted with one or more groups listed in the definition of Tl-lg, T2- and T', preferably selected from cyano, halo, oxo, hydroxy,-OT6,-C (O) tT6, -OC (O) T6-T4-NT7T8,-T4-N (T9)-T5-T6,-S (O) tT6 or-S (O) tN (T9) T.

The term"alkylene"refers to a straight chain bridge of 1 to 4 carbon atoms connected by single bonds (e. g.,- (CH2) x- wherein x is 1 to 5), which may be substituted with one or more groups listed in the definition of Tl-lg, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy,-OT6,-C (O) tT6,-OC (O) T6, -T4-NT7T8,-T4-N (T9)-T5-T6,-S (O) tT6 or-S (O) tN (T9) T6.

The term"alkenylene"refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with one or more groups listed in the definition of Tl-lg, T and T3-3g, preferably selected from cyano, halo, oxo, hydroxy, -OT6, -C(O)tT6, -OC(O)T6,

-T4-NT7T8,-T4-N (T9)-T5-T6,-S (O) tT6 or-S (O) tN (T9) T6. Exemplary alkenylene groups are-CH=CH-CH=CH-,-CH2-CH=CH-,-CH2-CH=CH-CH2-, -C (CH3) 2CH=CH- and -CH(C2H5)-CH=CH-.

The term"alkynylene"refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with one or more groups listed in the definition of Tl-lg, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy,-OT6,-C (O) tT6,-OC (O) T6, -T4-NT7T8, -T4-N(T9)-T5-T6, -S(O)tT6 or -S(O)tN(T9)T6. Exemplary alkynylene groups are-C= C-,-CH2-C= C-,-CH (CH3)-C= C-and -C#C-CH(C2H5)CH2-.

The terms"ar"or"aryl"refer to aromatic homocyclic (i. e. , hydrocarbon) mono-, bi-or tricyclic ring-containing groups preferably having 6 to 14 members such as phenyl, naphthyl and biphenyl, as well as such rings fused to a cycloalkyl, cycloalkenyl, heterocyclo, or heteroaryl ring. Examples include: and the like.

The term"substituted aryl"refers to aryl groups substituted with one or more groups listed in the definition of T1-1g, T2-2g and T3-3g, preferably selected cyano, halo, oxo, hydroxy,-OT6,-C (O) tT6,-OC (O) T6,-T4-NT7T8,-T4-N (T9)-T5-T6 -S(O)tT6 or -S(O) tN (T9) T.

The term"cycloalkyl"refers to saturated and partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons forming the ring, and which may be fused to 1 or 2 aromatic or heterocyclo rings, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

and the like. The terms"substituted cycloalkyl"refers to cycloalkyl groups substituted with one or more groups listed in the definition of Tl-lg, T'-'g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy,-OT6,-C (O) tT6,-OC (O) T6,-T4-NT7T8, - N (T9)-T-T,-S (O) tT or-S (O) tN (T9) T6.

The terms"halogen"and"halo"refer to fluorine, chlorine, bromine and iodine.

The terms"heterocycle", "heterocyclic","heterocyclyl","heterocyclic group" or"heterocyclo"refer to fully saturated or partially or unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, preferably containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1,2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be substituted or quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. The rings of multi-ring heterocycles may be either fused, bridged and/or joined through one or more spiro unions. Exemplary heterocyclic groups include

and the like.

The terms"substituted heterocycle", "substituted heterocyclic","substituted heterocyclic group"and"substituted heterocyclo"refer to heterocycle, heterocyclic and heterocyclo groups substituted with one or more groups listed in the definition of Tl-lg, T2-2g and T3-3g, preferably selected from cyano, halo, oxo, hydroxy,-OT, -C(O)tT6, -OC(O)T6, -T4-NT7T8, -T4-N(T9)-T5-T6, -S(O)tT6 or - (O) N (T9) T The term"heteroaryl"as used herein alone or as part of another group refers to a 5-6-or 7-membered aromatic rings containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided that the ring contains at least 1 carbon atom and no more than 4 heteroatoms. The heteroaryl ring is linked through an available carbon or nitrogen atom. Also included within the definition of heteroaryl are such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or another heteroaryl ring. One, two, or three available carbon or nitrogen atoms in the heteroaryl ring can be optionally substituted with substituents listed in the description of T1, T'and T3. Also an available nitrogen or sulfur atom in the heteroaryl ring can be oxidized. Examples of heteroaryl rings include

Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

The compounds of the present invention form salts which are also within the scope of this invention. Reference to a compound of the present invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt (s) ", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of formula I contains both a basic moiety and an acidic moiety, zwitterions ("inner salts") may be formed and are included within the term"salt (s)" as used herein. Pharmaceutically acceptable (i. e. , non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e. g. , in isolation or purification steps which may be employed during preparation. Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount,

in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

The compounds of the present invention which contain a basic moiety may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2- hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

The compounds of the present invention which contain an acidic moiety may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.

Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e. g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e. g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e. g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e. g. benzyl and phenethyl bromides), and others.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term"prodrug", as employed herein, denotes a compound

which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof. Solvates of the compounds of formula I are preferably hydrates.

To the extent that compounds of the the present invention, and salts thereof, may exist in their tautomeric form, all such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the various R and Z substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.

The terms"including", "such as", "for example"and the like are intended to refer to exemplary embodiments and not to limit the scope of the present invention.

SCHEMES Compounds of the formula I may be prepared using the sequence of steps outlined below.

SCHEME 1 Compounds of the formula I may be prepared using the sequence of steps outlined in scheme 1. Specifically, compounds of the formula I where R2 is heteroaryl or substituted heteroaryl and R5 is aryl, substituted aryl, heteroaryl or substituted heteroaryl may be prepared using Scheme 1. Heteroaryl acetonitrile 1 is deprotonated and alkylated to form the N-protected piperidine ring 2. Reduction of nitrile 2 generates primary amine 3. The amine is subsequently acylated with Heterocyle2 acyl chloride, deprotected and the resulting amine is taken onto final product carbamates, sulfonamides, sulfenyl ureas and cyanoguanidines.

Compounds of formula I where R3 is Z1 is O and R5 is-NR6aR7a may be prepared as described in Scheme 2.

SCHEME 2 OH p,/OH.,. NRR R \\O protecting R2 HNR6aRa R2 O 6- N group (PG) ion coupling N H PG agent PG 1 2 3 .., r) 6an7a o 9 !. NRR 6a 7a 6a 7a 2 deprotection 0 R OH 0 n o N coupling agent R 4 5 5

Protection of the nitrogen atom of compound 1 gives compound 2. One skilled in the art will recognize a variety of nitrogen protecting groups that are known in the literature. In this example, suitable nitrogen protecting groups include the benzyl (Bn), N-tert-butoxycarbonyl (Boc) and carbobenzyloxy (CBz) groups. The carboxylic acid moiety of compound 2 may be coupled with an amine HNR6aR7a using a variety of coupling procedures known in the literature to provide carboxamide compound 3. The nitrogen atom of compound 3 may be deprotected and made to react with a carboxylic acid (e. g.; R4C02H ; shown in Scheme 1) in the presence of a coupling agent or an acid chloride (e. g.; R4COC1) in the presence of an acid scavenger such as triethylamine or polystyrene-diisoproplyethylamine resin to give compound 5 where Q is NRl and Rl is- In addition to carboxylic acids or acid chlorides, one skilled in the art will recognize that the piperidine nitrogen atom of compound 4 may be made to react with a number of other readily available raw materials to provide compounds of formula I. For example, compound 4 may be made to react with sulfonyl chlorides (e. g.; R$SO2Cl) in the presence of an acid scavenger to provide compounds of formula I where Q is NR'and R'is Compound 4 may made to react with isocyanates (e. g.; R7R6NCO) to provide compounds of formula I where Q is NR'and R'is Compound 4 may be made to react

with chloroformates (e. g.; R4OCOCl) in the presence of an acid scavenger to provide compounds of formula I where Q is NR'and R'is Compound 4 may be made to react with certain heteroaryl groups (e. g; heteroaryl-X where X is a leaving group such as a halogen atom) in the presence of an acid scavenger to provide compound 5 where Q is NR'and R'is heteroaryl. This reaction is may be performed in an organic solvent such a tetrahydrofuran or acetonitrile at elevated temperatures.

Alternatively, this reaction may be performed in the presence of a palladium catalyst to provide compound 5 where Q is NR'and R'is heteroaryl.

Additional compounds of formula I where R3 is , Z1 isOandR5is- NR6aR7a may be prepared using as described in Scheme 3 and Scheme 4.

SCHEME 3 Referring to Scheme 2, compound 1 may be made to react with diphenyl N cyanocarbonimidate in a solvent such as tetrahydrofuran, acetonitrile or isopropanol to provide compound 2. Typically this reaction is conducted at elevated temperatures.

Compound 2 may be made to react with an amine HNR6R7 to provide cyano guanidine compound 3 where Q is NR'and R'is -NR6R7 and W is N-CN.

SCHEME 4

Referring to Scheme 3, compound 1 may be made to react with compound 2 to provide sulfenyl urea compound 3 where Q is NR'and R'is Compound 2 may be prepared by reacting 2-chloroethanol with chlorosulfonyl isocyanate followed by an amine HNR6R7 in the presence of an acid scavenger such as triethylamine in an organic solvent such as dichloromethane. One skilled in the art will recognize certain sulfenyl ureas may be prepared from commercially available raw materials. For example, compound 1 may be made to react with dimethylsulfamoyl chloride in a solvent such as tetrahydrofuran or dichloromethane in the presence of an acid scavanger such as triethylamine or polystyrene- diisopropylethylamine resin to provide compound 3 where Q is NRl and Rl is and R6 and R7 are each methyl. Compound 1 may be made to react with sulfamide in a solvent such as 1,4-dioxane at elevated temperature to provide compound 3 where Q is NR1 and Rl is and R6 and R7 are each hydrogen.

Compounds of formula I where J is Cl-alkylene (e. g.; CH2), R3 is is O and R5is-NR is -NR6aR7a may be prepared using as described in Scheme 5.

SCHEME 5 a2 GOsH 9 No p/OH 1. SOCI2 1. UV light O IN 2. diazomethane N 2. LiOH IN PG PG 1, 3 NR6aR7a NR6aR7a R2 HNR6aRa R2 \\ 1. deprotection \O O coupling N 2. nitrogen derivatization X zt agent PG 5 4 The carboxylic acid compound 1 may be treated with thionyl chloride to convert the carboxylic acid to the acid chloride that is made to react with diazomethane in a solvent such as ethyl ether to produce a diazo intermediate compound 2. Compound 2 may be irradiated under ultra-violet light (k = 365 nM) in a solvent such as methanol to provide an ester that may be hydrolyzed to the carboxylic acid compound 3 by treatment with aqueous lithium hydroxide. The carboxylic acid moiety of compound 3 may be coupled with an amine HNR6aR7a using a variety of coupling procedures known in the literature to provide carboxamide compound 4. The nitrogen atom of compound 3 may be deprotected and the nitrogen atom further derivatized (see Schemes 1-3) to provide compounds of formula I.

Compounds of formula I where J is a bond, R3 is Zliso, R5is- NR6aR7a and R8a is hydrogen may be prepared using as described in Scheme 6.

SCHEME 6

Compound 1 may be made to react with diphenylphosphoryl azide in a solvent such as chlorobenzene at an elevated temperature to produce isocycanate compound 2.

Compound 2 may be made to react with an amine HNR6aR7a to produce the urea compound 3 where J is a bond, R3 is Z1 is O, R5 is -NR6aR7a and R8a is hydrogen.

Compounds of formula I where J is a bond, R3 is Zl is O and R8a is hydrogen may be prepared using as described in Scheme 7.

SCHEME 7 Isocyanate compound 1 may be made to react with an alcohol ROH in a solvent such as chlorobenzene or terahydrofuran to provide compound 2 where J is a bond, R3 is Zl is O and R8a is hydrogen.

Compounds of formula I where J is a bond, R3 is Z1 is O, R5 is not NR6aR7a and R8a is hydrogen may be prepared using as described in Scheme 8.

SCHEME 8 2 H 0_ 0 H R 5 f H R5 R N \\ O \ N Rs INI TFA R5 OH O N N R R1 coupilng R agent 1 2 3 Compound 1 (see Scheme 6; R5 is tert-butyl) may be deprotected by treatment with trifluoroacetic acid in a solvent such as dichloromethane to provide amine compound 2. The amino group of compound 2 may be made to react with a carboxylic acid (e. g.; R5CO2H ; shown in Scheme 7) in the presence of a coupling agent or an acid chloride (e. g.; R5COCl) in the presence of an acid scavenger such as triethylamine or polystyrene-diisoproplyethylamine resin to give compound 3 where J is a bond, R3 is Z is O, R5 is not NR6aR7a and R8a is hydrogen In addition to carboxylic acids or acid chlorides, one skilled in the art will recognize that compound 2 may be made to react with a number of other readily available raw materials to provide compounds of formula I. For example, compound 2 may be made to react with sulfonyl chlorides (e. g.; R5SO2Cl) in the presence of an acid scavenger to provide compounds of formula I where J is a bond and R3 is Compounds of formula I where R3 is R5, R5 is NR 6a R7'and R6, is heteroaryl may be prepared as described in Scheme 9.

SCHEME 9 , heteroaryl R2 NH2 heteroaryl-X R2 \H N N R R 1 2

Amine compound 1 may be made to react with a substituted aryl or heteroaryl compound where X is a halogen atom, triflate or similar leaving group to provide compound 2. This reaction may be conducted in an organic solvent such a tetrahydrofuran or acetonitrile at an elevated temperature. Alternatively, this reaction may be performed in the presence of a palladium catalyst to provide compound 2 where R3 is R5, R5 is NR6aR7a and R6a is heteroaryl.

Compounds of formula I where R3 is R5 and R is heteroaryl may be prepared as described in Scheme 10 and Scheme 11.

SCHEME 10 Referring to Scheme 9, acid chloride compound 1 may be made to react compound 2 in an organic solvent such as dichlormethane to provide carboxamide compound 3. Cyclization of compound 2 in the presence of an acid such as acetic acid at elevated temperature provides compound 3 where R3 is R5 and R5 is heteroaryl (e. g.; benzimidazole). One skilled in the art will recognize that carboxylic acids or acid chlorides may be converted to a wide variety of heteroaryl groups. For example, compound 1 may be made to react with a 2-amino phenol to provide compounds of

formula I where R3 is R5 and R5 is heteroaryl (e. g.; benzoxazole). Compound 1 may be made to react with a 2-amino benzenethiol to provide compounds of formula I where R3 is R5 and R5 is heteroaryl (e. g.; benzthiazole). Compound 1 may be made to react with an N-hydroxyamidine to provide compounds of formula 3 where R3 is R5 and R5 is heteroaryl (e. g.; oxadiazole).

SCHEME 11 Referring to Scheme 10, cyano compound 1 may be made to react with sodium azide in a solvent such as methyl sulfoxide at elevated temperatures to provide tetrazole compound 2. Compound 2 may be made to react with T1c-X where X is a leaving group such as a halogen atom or triflate to provide compound 3 where R3 is R5 and R5 is heteroaryl (e. g.; tetrazole).

Compounds of formula I where R2 is alkyl, cycloalkyl or (aryl) alkyl may be prepared as described in Scheme 12.

SCHEME 12 CN CN protecting N group N H iIiG 1 2 R 2x I LDA R2 C02H NaOH R2 CN LAH R2 NH2 N N N PG PG PG 5 3 4 5 Protection of the nitrogen atom of compound 1 provides compound 2.

Deprotonation of compound 2 with a base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran a low temperature followed by reaction with a benzyl halide, for example, provides compound 3 where R2 is (aryl) alkyl. One skilled in the art will recognize that aldehydes and ketone may also be made to react with compound 2 after deprotoation with lithium diisopropylamide. The cyano group of compound 3 may be reduced with lithium aluminum hydride in a solvent such as tetrahydrofuran to provide amino compound 4. Alternatively, the cyano group of compound 3 may be hydrolyzed with aqueous sodium hydroxide to provide carboxylic acid compound 5. Compounds of formula I may be prepared from compounds 4 and 5 as described previously.

SCHEME 13

Compounds of the formula 1 where p = 3, m = 2, Q = NR1, R2 = aryl may be prepared as described in Scheme 13. The lactam was prepared from intermediate cyclohexanone which was synthesized as described in Journal of Medicinal Chemistry, 1998,821. The lactam nitrogen was protected using standard protecting group methodology and the lactam carbonyl group and the nitrile group were reduced either simultaneously or subsequently. The primary amine was acylated, the protecting group was removed and the azapene was further functionalized to the sulfinyl urea, the carbamate, the amide or alkylated directly.

SCHEME 14 Cl Cl I J 2 2 p 'p reduction \r R CN O R CN reduction R NH cylicaztion 1 2 3 3 2 O 1 2 3 R ph coupling agent 4 Compounds of formula I where Q is O, R3 is Zl is O, and R8a is

hydrogen may be prepared as described in Scheme 14. Compound 1 may be made to react with bis (2-chloroethyl) ether under phase-transfer catalysis conditions to provide the cyclized product compound 2. The nitrile group of compound 2 may be reduced using various methods, including treatment with lithium aluminum hydride or hydrogenation in the presence of platinum (IV) oxide, to provide the amine compound 3. The amino group of compound 3 may be made to react with a carboxylic acid (e. g.; R5Co2H) in the presence of a coupling agent in an organic solvent such as tetrahydrofuran to provide the acylated product compound 4.

Additional compounds within the scope of the present invention can be prepared from the compounds obtained by the above described methods through conversion of the substituent groups to other functionality by the usual methods of chemical synthesis, as illustrated in the following examples.

Compounds of formula I that contain chiral centers may be obtained in non- racemic form by non-racemic synthesis or resolution by methods well known to those skilled in the art. Compounds that are non-racemic are designated as"chiral"in the examples.

In the examples described below it may be necessary to protect reactive functionality such as hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in reactions. The introduction and removal of protecting groups are well known to those skilled in the art, for example see (Green, T. W. in"Protective Groups in Organic Synthesis", John Wiley and Sons, 1991).

Utility Compounds within the scope of the present invention inhibit the Kl subfamily of voltage-gated K+ channels, and as such are useful in the treatment and/or prevention of various disorders: cardiac arrhythmias, including supraventricular arrhythmias, atrial arrhythmias, atrial flutter, atrial fibrillation, complications of cardiac ischemia, and use as heart rate control agents; angina pectoris including relief

of Prinzmetal's symptoms, vasospastic symptoms and variant symptoms; gastrointestinal disorders including reflux esauphagitis, functional dispepsia, motility disorders (including constipation and diarrhea), and irritable bowel syndrome; disorders of vascular and visceral smooth muscle including asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease; inflammatory and immunological disease including inflammatory bowel disease, rheumatoid arthritis, graft rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis and atherosclerosis; cell poliferative disorders including restenosis and cancer (including leukemia); disorders of the auditory system; disorders of the visual system including macular degeneration and cataracts; diabetes including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy; muscle disease including myotonia and wasting; peripheral neuropathy; cognitive disorders; migraine; memory loss including Alzheimer's and dementia; CNS mediated motor dysfunction including Parkinson's disease, and ataxia; epilepsy; and other ion channel mediated disorders.

As inhibitors of the KV1 subfamily of voltage-gated K+ channels compounds of the present invention are useful to treat a variety of disorders including resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation, rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenicmicroorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, heretic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic

asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Good-pasture's syndrome, hemolytic- uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-BalTe syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia osses dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy; Pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenis, metastatis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-

A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic"liver failure, augention of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

The compounds of the present invention are antiarrhythmic agents which are useful in the prevention and treatment (including partial alleviation or cure) of arrhythmias. As inhibitors of Kvl. 5 compounds within the scope of the present invention are particularly useful in the selective prevention and treatment of supraventricular arrhythmias such as atrial fibrillation, and atrial flutter. By"selective prevention and treatment of supraventricular arrhythmias"is meant the prevention or treatment of supraventricular arrhythmias wherein the ratio of the prolongation of the atrial effective refractory period to the prolongation of the ventricular effective refractory period is greater than 1: 1. This ratio is preferably greater than 4: 1, more preferably greater than 10: 1, and most preferably such that prolongation of the atrial effective refractory response period is achieved without significantly detectable prolongation of the ventricular effective refractory period.

In addition, the compounds within the scope of the present invention block Inur. and thus may be useful in the prevention and treatment of all IKur-associated conditions. An"IK"r-associated condition"is a disorder which may be prevented, partially alleviated or cured by the administration of an Inur blocker. The Kvl. 5 gene is known to be expressed in stomach tissue, intestinal/colon tissue, the pulmonary artery, and pancreatic beta cells. Thus, administration of an Inur blocker could provide useful treatment for disorders such as: reflux esauphagitis, functional dispepsia, constipation, asthma, and diabetes. Additionally, Kvl. 5 is known to be expressed in the anterior pituitary. Thus, administration of an IKur blocker could stimulate growth hormone secretion. Isur inhibitors can additionally be useful in cell poliferative disorders such as leukemia, and autoimmune diseases such as rheumatoid arthritis and transplant rejection.

The present invention thus provides methods for the prevention or treatment of one or more of the aforementioned disorders, comprising the step of administering to a subject in need thereof an effective amount of at least one compound of the present invention. Other therapeutic agents such as those described below may be employed

with the inventive compounds in the present methods. In the methods of the present invention, such other therapeutic agent (s) may be administered prior to, simultaneously with or following the administration of the compound (s) of the present invention.

The present invention also provides pharmaceutical compositions comprising at least one of the compounds of the present invention or salts thereof capable of preventing or treating one or more of the aforementioned disorders in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc. ) according to techniques such as those well known in the art of pharmaceutical formulation.

The compounds of the present invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e. g. , as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. In the case where the compounds of formula I are being administered to prevent or treat arrhythmias, the compounds may be administered to achieve chemical conversion to normal sinus rhythm, or may optionally be used in conjunction with electrical cardioconversion.

Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid

or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of formula I may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound (s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e. g. , Gantrez), and agents to control release such as polyacrylic copolymer (e. g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.

Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono-or diglycerides, and fatty acids, including oleic acid.

Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.001 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to the aforementioned disorders.

The compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of the aforementioned disorders or other disorders, including: other antiarrhythmic agents such as Class I agents (e. g., propafenone), Class II agents (e. g., carvadiol and propranolol), Class in agents (e. g. , sotalol, dofetilide, amiodarone, azimilide and ibutilide), Class IV agents (e. g. , diltiazem and verapamil), 5HT antagonists (e. g. , sulamserod, serraline and tropsetron), and dronedarone; calcium channel blockers (both L-type and T-type) such as diltiazem, verapamil, nifedipine, amlodipine and mybefradil; Cyclooxygenase inibitors (i. e. , COX-1 and/or COX-2 inhibitors) such as aspirin, indomethacin, ibuprofen, piroxicam, naproxen, celebrex, vioxx and NSAIDs ; anti-platelet agents such as GPIIb/IQa blockers (e. g. , abciximab, eptifibatide and tirofiban), P2Yl2 antagonists (e. g. , clopidogrel, ticlopidine and CS- 747), thromboxane receptor antagonists (e. g. , ifetroban), aspirin, and PDE-E inhibitors (e. g. , dipyridamole) with or without aspirin; diruetics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,

bumetanide, triamtrenene, amiloride, and spironolactone; anti-hypertensive agents such as alpha adrenergic blockers, beta adrenergic blockers, calcium channel blockers, diuretics, renin inhibitors, ACE inhibitors, (e. g. , captropril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), A II antagonists (e. g. , losartan, irbesartan, valsartan), ET antagonists (e. g. sitaxsentan, atrsentan and compounds disclosed in U. S. Patent Nos. 5,612, 359 and 6,043, 265), Dual ET/AII antagonist (e. g. , compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e. g. , omapatrilat and gemopatrilat), nitrates, and combinations of such anti- hypertensive agents; antithrombotic/thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA), factor Vila inhibitors, factor Xa inhibitors, thromin inibitors (e. g. , hirudin and argatroban), PAI-1 inhibitors (i. e. , inactivators of tissue plasminogen activator inhibitors), a2-antiplasmin inhibitors, streptokinase, urokinase, prourokinase, anisoylated plasminogen streptokinase activator complex, and animal or salivary gland plasminogen activators; anticoagulants such as warfarin and heparins (including unfractionated and low molecular weight heparins such as enoxaparin and dalteparin); HMG-CoA reductase inhibitors such as pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a. k. a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a. k. a. rosuvastatin, or atavastatin or visastatin); other cholesterol/lipid lowering agents such as squalene synthetase inhibitors, fibrates, and bile acid sequestrants (e. g. , questran); antipoliferative agents such as cyclosporin A, taxol, FK 506, and adriamycin; antitumor agents such as taxol, adriamycin, epothilones, cisplatin and carboplatin; anti-diabetic agents such as biguanides (e. g. metformin), glucosidase inhibitors (e. g. acarbose), insulins, meglitinides (e. g. repaglinide), sulfonylureas (e. g. glimepiride, glyburide and glipizide), biguanide/glyburide combinations (i. e,. glucovance), thiozolidinediones (e. g. troglitazone, rosiglitazone and pioglitazone), PPAR-gamma agonists, aP2 inhibitors, and DP4 inhibitors; thyroid mimetics (including thyroid receptor antagonists) (e. g. , thyrotropin, polythyroid, KB-130015, and dronedarone); Mineralocorticoid receptor antagonists such as spironolactone and eplerinone ; growth hormone secretagogues; anti-osteoporosis agents (e. g. , alendronate and raloxifene); hormone replacement therapy agents such as estrogen (including conjugated estrogens

in premarin), and estradiol; antidepressants such as nefazodone and sertraline ; antianxiety agents such as diazepam, lorazepam, buspirone, and hydroxyzine pamoate; oral contraceptives; anti-ulcer and gastroesophageal reflux disease agents such as famotidine, ranitidine, and omeprazole; anti-obesity agents such as orlistat; cardiac glycosides including digitalis and ouabain; phosphodiesterase inibitors including PDE III inhibitors (e. g. cilostazol), and PDE V inhibitors (e. g. , sildenafil); protein tyrosine kinase inhibitors; steroidal anti-inflammatory agents such as prednisone, and dexamethasone; and other anti-inflammatory agents such as enbrel.

The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians'Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

Assays to determine the degree of activity of a compound as an Isur inhibitor are well known in the art and are described in references such as J. Gen. Physiol.

Apr; 101 (4): 513-43, andBr. J. Pharmacol. l995May ; 115 (2): 267-74.

Assays to determine the degree of activity of a compound as an inhibitor of other members of the K, I subfamily are also well known in the art. For example, inhibition of Kvl. l, Kvl. 2 and K, 1.3 can be measured using procedures described by Grissmer S, et al., Mol Pharmacol 1994 Jun; 45 (6): 1227-34. Inhibition of Kvl. 4 can be measured using procedures described by Petersen KR, and Nerbonne JM, Pflugers Arch 1999 Feb ; 437 (3): 381-92. Inhibition of Kvl. 6 can be measured using procedures described by Bowlby MR, and Levitan IB, J Neurophysiol 1995 Jun; 73 (6): 2221-9.

And inhibition of Kvl. 7 can be measured using procedures described by Kalman K, et al., JBiol (Chem 1998 Mar 6; 273 (10): 5851-7.

Compounds within the scope of the present invention demonstrate activity in Kvl assays such as the ones described above.

All documents cited in the present specification are incorporated herein by reference in their entirety.

The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto.

EXAMPLES EXAMPLE 1 2-Methoxy-N- (4-thiophen-2-yl-piperidin-4-ylmethyl)-benzamide Synthesis Cl Cl Clß Cl 2-thiophene S X benzoylchloride J (acetonitrile \/ N N H TEA/DCM NaH, DMF Im O 1 2 3 9 LAH/THF I 69NJA 0 O II/ N NH2 \/H I 1) chloroethyl \/N \/NH2 I H itOi chloroformate Anisoyl chloride J SN N TEA/DCM N H 2) MeOH 65 4 Compound 1: Compound 1 is commercially available.

Compound 2: Compound 1 (20 g, 0.11 mol) was suspended in 200 mL dichloromethane. Benzoylchloride (17 mL, 0.14 mol) was added. At 0 °C TEA (42 mL, 0. 30mol) in dichloromethane (10 mL) was added slowly to the reaction mixture.

The reaction mixture was stirred at room temperature for 14 h, diluted with Ethyl acetate (500 mL), washed with saturated NaHC03 (2 x 250 mL), IN HC1 (2 x 250 mL), dried over MgS04, filtered and concentrated. The residue was purified by silica gel chromotography using Hexanes/Ethyl acetate (4/1,1/1) as eluent to give an orange oil compound 2,25. 85 g (94% yield).

Compound 3: NaH (6.0 g, 0.25 mol) was suspended in DMF (100 mL). At 0 °C 2-thiopheneacetonitrile (7.5 g, 0.061 mol) was added followed by the addition of compound 2 (12 g, 0.048 mol) in 100 mL DMF. The reaction was stirred at 0 °C for 0.5 h and then at ambient temperature for 14 h. The reaction mixture was poured into ice and extracted with Ethyl acetate (250 mL). The aqueous layer was extracted with Ethyl acetate (2 x 250 mL). The organic layers were combined and washed with 10% LiCl (2 x 200 mL), dried over MgS04, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with 2/1 and 1/1 Hexane: Ethyl acetate yielding 9.14 g (64% isolated yield) of compound 3 as a dark brown solid.

HPLC Rt 2.87 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.47 min, [M+1] 297.22 Phenomenex S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1 % TFA) UV detection at 220nm. NMR H (CDC13) 1.74- 2.32 ppm, 4H, m; 3. 22- 3. 43 ppm, 2H, m; 3.78-3. 84 ppm, 1H, broadpeak; 4.79 ppm, 1H, broad peak; 6.94 ppm, 1H, dd, J=5.0 Hz and 3.6 Hz; 7.08 ppm, 1H, dd, J=3.3 Hz and 1.1 Hz; 7.24 ppm, 1H, dd, J=5.0 Hz and 1.1 Hz; 7.34-7. 42 ppm, 5H, m.

Compound 4: To a solution of compound 3 (2.1 g, 7.2 mmol) in THF (40 mL) was added LAH (20 mL, 20 mmol, 1. OM solution in THF). The reaction mixture was heated to reflux for 1 h then allowed to cool to ambient temperature. The solution was cooled to 0 °C and quenched with water (5.3 mL), IN NaOH (3.4 mL) and water (5.3 mL). The quenched reaction mixture was stirred at ambient temperature for 0.5 h. The slurry was filtered through a celite pad and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL), washed with saturated NaHC03 (2 x 100 mL), dried over MgS04, filtered and concentrated to give a brown oil compound 4 sufficiently pure to be taken on to the next step. HPLC Rt 0.20 min and 0.59 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 0.73 min, [M+1] 287.39 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.85 ppm, 2H, m; 2.05-2. 08 ppm, 2H, m; 2.22-2. 27 ppm, 2H, m; 2.67 ppm, 1H, s; 2.69 ppm, 2H,

m; 3.44 ppm, 2H, s; 6.77-6. 78 ppm, 1H, m; 6.94 ppm, 1H, dd, J=5.0 Hz and 3.3 Hz; 7.17-7. 30ppm, 6H, m.

Compound 5: Compound 4 was dissolved in dichloromethane (30 mL) and ortho-anisoyl chloride (1.1 mL, 7.4 mmol) was added followed by the addition of TEA (2.3 mL, 16 mmol). The reaction was stirred at ambient temperature for 14 h, diluted with dichloromethane (200 mL), washed with saturated NaHC03, dried over MgS04, filtered and concentrated. The product amide compound 5 was eluted with 2: 1 and 1 : 1 hexane: ethylacetate as a white foam (2.19g, 77% yield for two steps).

HPLC Rt 2.50 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.36 min, [M+1] 421.27 Phenomenex S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CD30D) 1.98- 2.00 ppm, 2H, m; 2.15-2. 18 ppm, 2H, m; 2.44 ppm, 2H, m; 2.74-2. 76 ppm, 2H, m; 3.53 ppm, 2H, s; 3.65 ppm, 2H, s; 3.77 ppm, 3H, s; 7. 02-7. 09 ppm, 4H, m; 7.25 - 7. 31 ppm, 5H, m; 7.39-7. 40 ppm, 1H, m; 7.45-7. 48ppm, 1H, m; 7.93-7. 95 ppm, 1H, m.

Compound 6: Compound 5 (2.2 g, 5.2 mmol) was dissolved in dichloroethane (40 mL) and TEA (3.6 mL, 26 mmol) was added. At 0 °C chloroethyl chloroformate (1.1 mL, 10 mmol) in dichloroethane (20 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h, then another 1.1 mL chloroethyl chloroformate in dichloroethane (20 mL) was added. The reaction was stopped till no starting material left according to LC-MS. The reaction mixture was concentrated and dried on oil pump for 0.5 h. MeOH (40 mL) was added to the residue and was heated to reflux for 4 h. The reaction mixture was concentrated and the residue was purified by a silica gel pad eluted with 1 : 1 EtOAc: Hexane and then 1: 1 MeOH : DCM yielding a pale yellow solid 2-methoxy-N- (4-thiophen-2-yl-piperidin-4-ylmethyl)-benzamide 6 (1.63 g, 95% yield). HPLC Rt 2.09 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm.

LCMS Rt 1.20 min, [M+1] 331.41 Phenomenex S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220nm. NMR H (CDC13) 2.01-2. 04 ppm, 2H, m; 2.14-2. 18 ppm, 2H, m; 2.92-2. 94 ppm, 2H,

m; 3.16 ppm, 2H, m ; 3.64 ppm, 2H, s; 3.67 ppm, 3H, s; 6.82-6. 86 ppm, 2H, m; 6. 96- 7. 00 ppm, 2H, m; 7.23-7. 25 ppm, 1H, m; 7.32-7. 37 ppm, 1H, m; 8.09- 8. 11 ppm, 1H, m.

EXAMPLE 2 4- [(2-Methoxy-benzoylamino)-methyl]-4-thiophen-2-yl-piperidine - 1-carboxylic acid ethyl ester Synthesis . c 0 0 W N H I ethyl chloroformate H --r j u) J NJ TEA, DCM N H H 2 2 Compound 1: Compound 1 was prepared using methodology described in Example 1.

Compound 2: Compound 1 (14 mg, 0.043 mmol) was dissolved in dichloromethane (0.20 mL). At ambient temperature TEA (12 uL, 0.086 mmol) was added followed by the addition of ethyl chloroformate (4.90 mg, 0.045 mmol) in dichloromethane (0.10 mL). The reaction mixture was stirred for 2.5 h and then concentrated. 4-[(2-Methoxy-benzoylamino)-methyl]-4-thiophen-2-yl-piperidi ne-1- carboxylic acid ethyl ester 2 (13.7 mg, 79% yield) was isolated by Prep-HPLC as a colorless oil. HPLC Rt 3.43 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm.

LCMS Rt 1.78 min, [M+1] 403.17 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.18 ppm, 3H, t, J=7.1 Hz; 1. 81-1. 84 ppm, 2H, m; 2.00-2. 04 ppm, 2H, m; 3.18- 3.2 5ppm, 2H, m; 3.67 ppm, 3H, s; 3.73-3. 77 ppm, 4H, m; 4.05 ppm, 2H, q, J=7.1 Hz; 6.83-6. 88 ppm, 2H, m; 6.98-7. 02 ppm, 2H, m; 7.25 ppm, 1H, dd, J=5.0 Hz and 0.76 Hz; 7.34-7. 39 ppm, 1H, m; 7.83 ppm, 1H, m; 8.10 ppm, 1H, dd, J=7.8 Hz and 1.7 Hz.

EXAMPLE 3 Example 3 was prepared using methodology described in Example 2. Example Structure Name [M+1] 3 s 0 oll 4- [ (2-Methoxy-benzoylamino)-methyl]-4- 430 x/) N, thiophen-2-yl-piperidine-l-carboxylic acid test-butyl ester j't N EXAMPLE 4

2-Methoxy-N-[l-(propane-1-sulfonyl)-4-thiophen-2-yl-piperidi n- 4-ylmethyl]-benzamide Synthesis 0 0 s o o s S n < /<N Propyl sulfonylchloride NJ/ k,. ""TEA, DCM N H 0

1 2 Compound 1: Compound 1 was prepared using methodology described in Example 1.

Compound 3: Compound 1 (14 mg, 0.043 mmol) was dissolved in dichloromethane (0.20 mL). At ambient temperature TEA (12 uL, 0.086 mmol) was added followed by the addition of propyl sulfonylchloride (6.4 mg, 0.045 mmol) in dichloromethane (0.10 mL). The reaction mixture was stirred for 1 h and then concentrated. 2-Methoxy-N- [1- (propane-1-sulfonyl)-4-thiophen-2-yl-piperidin-4- ylmethyl] -benzamide (14.5 mg, 77% yield) was isolated by Prep-HPLC as a colorless oil. HPLC Rt 3.21 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.67 min, [M+1] 437.15 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 0.97 ppm, 3H, t, J=7.5 Hz; 1.73-1. 79 ppm, 2H, m; 1.92-1. 98 ppm, 2H, m; 2.09-2. 14 ppm, 2H, m; 2.78-2. 82 ppm, 2H, m; 3.19-3. 25 ppm, 2H, m; 3.40-3. 45 ppm, 2H, m; 3.66 ppm, 3H, s; 3.71 ppm, 2H, d, J=6.2 Hz; 6.84-6. 88 ppm, 2H, m; 6.99-7. 03 ppm, 2H, m; 7.27 ppm, 1H, dd, J=5.0 Hz and 0.74 Hz; 7.37-7. 41 ppm, 1H, m; 7.98 ppm, 1H, m; 8.07 ppm, 1H, dd, J=7.8 Hz and 1.8 Hz.

EXAMPLES 5 AND 6 Examples 5 and 6 were synthesized using methodology described in Example 4.

Example Structure Name [M+1] 5 s P ? N- (l-Benzenesulfonyl-4-thiophen-2-yl- 470 piperidin-4-ylmethyl)-2-methoxy- benzamide N O O. W 6 s o o'N- [1- (4-Fluoro-benzenesulfonyl)-4- 488 q HX thiophen-2-yl-piperidin-4-ylmethyl]-2- methoxy-benzamide N 0 F EXAMPLE 7

2-Methoxy-N- [4-thiophen-2-yl-1- (2, 2,2-trifluoro-ethylsulfamoyl)-piperidin- 4-ylmethyl]-benzamide Synthesis

5 Compound 1: Compound 1 is commercially available.

Compound 2: Compound 2 is commercially available.

Compound 3: Compound 1 (26 mg, 0.18 mmol) was dissolved in dichloromethane (0.50 mL). At 0 °C compound 2 (15 mg, 0.18 mmol) in dichloromethane (0.50 mL) was added and the reaction mixture was stirred for 1 h.

Trifluoroethylamine (18 mg, 0.18 mmol) in dichloromethane (0.50 mL) was added followed by the addition of TEA (75 uL, 0.54 mmol). The reaction mixture was stirred at ambient temperature for 2 h and then at 35 °C for 14 h. The reaction was diluted with dichloromethane (20 mL), washed with IN HC1 (10 mL), dried over MgS04, filtered and concentrated to yield compound 3 sufficient pure to be taken to the next step.

Compound 4: Compound 4 was prepared using methodology described in Example 1.

Title Compound: Compound 4 (20 mg, 0.060 mmol) and TEA (130 uL, 0.94 mmol) were dissolved into acetonitrile (1.0 mL). To this mixture compound 3 was added and the reaction mixture was heated at 95 °C for 14 h. The reaction was concentrated and the residue was purified by PrepHPLC yielding 2-methoxy-N- [4- thiophen-2-yl-l- (2, 2,2-trifluoro-ethylsulfamoyl)-piperidin-4-ylmethyl]-benzamid e (17.2 mg, 58% yield) as a clear oil. HPLC Rt 3.25 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA)

UV detection at 220nm. LCMS Rt 1.66 min, [M+1] 492.14 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.94-1. 96 ppm, 2H, m; 2.01-2. 12 ppm, 2H, m; 3. 11- 3. 13 pm, 2H, m; 3. 43 ppm, 2H, m; 3.56-3. 59 ppm, 2H, m; 3. 64 ppm, 2H, s; 3.66 ppm, 3H, s; 4.95 ppm, 1H, t, J=5.7 Hz; 6.85-6. 86 ppm, 2H, m; 6.99-7. 00 ppm, 2H, m; 7.25-7. 26 ppm, 1H, m; 7.35-7. 36 ppm, 1H, m; 7.75-7. 78 ppm, 1H, m; 8.12 ppm, 1H, dd, J=6.2 Hz and 1.3 Hz.

EXAMPLES 8 TO 14 Examples 8 to 14 were prepared using methodology described in Example 7. Example Structure Name [M+1] 8 s ? N-(l-Dimethylsulfamoyl-4-thiophen-2-437 62 N yl-piperidin-4-ylmethyl)-2-methoxy- benzamide N I O5=0 o=s=o 9 s ? °'N- [1- (4-Fluoro-benzylsulfamoyl)-4- 517 thiophen-2-yl-piperidin-4-ylmethyl]-2- methoxy-benzamide o=s=o N F 10 s o o' (4-Fluoro-benzyl)-carbamic acid 2-{4-604 6 tNX [(2-methoxy-benzoylamino)-methyl]-4- thiophen-2-yl-piperidine-1- _ sulfonylamino}-ethyl ester l tOAN <F CoN , 11 s j.' 2-Methoxy-N- (l-phenylsulfamoyl-4- 485 -2-yl-piperidin-4-ylmethyl)- "'benzamide 'p ut 12 s o o'2-Methoxy-N-(l-methylsulfamoyl-4-423 N 11-6 thiophen-2-yl-piperidin-4-ylmethyl)- benzamide o=s=o NU Example Structure Name [M+l] 13 S ° °'N- {1- [1- (4-Fluoro-phenyl)- 531 ethylsulfamoyl]-4-thiophen-2-yl- piperidin-4-ylmethyl}-2-methoxy- 0= F benzamide 14 s ° o'2-Methoxy-N- (l-propylsulfamoyl-4- 451 thiophen-2-yl-piperidin-4-ylmethyl)- benzamide o=s=o NEZ EXAMPLE 15

2-Methoxy-N- (4-phenyl-1-sulfamoyl-piperidin-4-ylmethyl)-benzamide Synthesis o o LiAIH4 NH2 N --. THF NEt3 H LJ THF [. J NEtg !] H ( ! j N N CH2CI2 N HCI b 1 2 3 1 2 3 H2, Pd/C EtOH 0 0 o o' Li H2N NH2 NJe N H I/ N /1, 4-Dioxane, AN ZUR H O=S=O NH2

5 Compound 1: Compound 1 is commercially available.

Compound 2: To l-N-benzyl-4-phenyl-4-cyanopiperidine. HCl (10.0 g, 31.97 mmol) was added 220 mL of THF and the reaction flask was cooled to 0°C. Lithium aluminum hydride (4.85 g, 127.86 mmol) was added slowly and the reaction mixed 12 h at room temperature. The reaction was quenched by the addition of 5 mL of water, 15 mL of 15% aqueous solution of sodium hydroxide followed by 5 mL of water.

The organic fraction was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give compound 2 that was used without further purification.

LCMS Rt 1.70 min, [M+1] 281.0.

Compound 3: To a solution of 1-N-benzyl-4-phenyl-4- aminomethylpiperidine (4.0 g, 14.26 mmol) and triethylamine (3.0 g, 21.39 mmol) in 18 mL of dichloromethane was added o-anisoyl chloride (425 iL, 2.85 mmol) at 0°C.

The reaction was stirred for 12 h and quenched with (100 mL) of 1 M hydrochloric acid. Dichloromethane (100 mL) was also added and the aqueous layer was washed with dichloromethane (50 mL portions, 2x). The organic fractions were combined and washed with 1 N sodium hydroxide (50 mL portions, 2x) followed by brine (100

mL). The organics were dried over anhydrous sodium sulfate and concentrated. 4.54 g (77% yield) of compound 3 was obtained. LCMS Rt 1.41 min, [M+1] 415.1.

Compound 4: To a solution of N-(l-benzyl-4-phenyl-piperidin-4-ylmethyl)- benzamide (4.54 g, 10.95 mmol) in ethanol (100 mL) was added 10% palladium/carbon (1.40 g). The reaction mixture was stirred in a hydrogen atmosphere (50 psi) for 78 h. After filtration, the filtrate was concentrated and purified using column chromatography o silica gel using 9: 1: 0.1 chloroform: methanol: ammonium hydroxide as the eluent to give a yellow oil. After lyophilization 2.7 g (76 % yield) of compound 4 as a white/yellow powdery solid was obtained. LCMS Rt 1.43 min, [M+1] 325.3.

Title Compound: To compound 4 (50 mg, 0.154 mmol) in 1,4-dioxane (1.7 mL) was added sulfamide (148 mg, 1.54 mmol) and then stirred at 100°C overnight.

The solution was cooled to room temperature and the solvent was concentrated under reduced pressure. The crude material was diluted with dichloromethane (10 mL) and washed with water (10 mL) (2x), brine (10 mL) (lx) and dried over Na2S04, filtered and concentrated under reduced pressure to give a white solid. The crude was purified using preparative HPLC and lyophilized to give 54 mg (87% yield) of 2- methoxy-N- (4-phenyl-1-sulfamoyl-piperidin-4-ylmethyl)-benzamide. 1H NMR (CDC13, rt): 8 ppm) 2.11-2. 19 (2 H, m), 2.22-2. 25 (2 H, m), 3.24-3. 26 (2 H, m), 3.35- 3.38 (2 H, m), 3.57 (3 H, s), 3.67 (2 H, d, J = 6 Hz), 4.43 (2 H, s), 6.86 (1 H, d, J = 8. 3 Hz), 7.05 (1 H, t, J = 7.5 Hz), 7.30-7. 45 (6 H, m), 7.63 (1H, s), 8. 16 (1 H, d, J = 7.5).

LCMS Rt 1.50 min, [M+1] 404.2.

EXAMPLE 16 N- (1-Dimethylsulfamoyl-4-phenyl-piperidin-4-ylmethyl)-2-methox y-benzamide Synthesis o o o \ I N 1) (CH3) 2NS02CI \ N I H THF, PS-DIEA N N 2) AP-Trisamine 1 zNX i y/N

2 Compound 1: Compound 1 was prepared as described in Example 15.

Title Compound: To compound 1 (35 mg, 0.108 mmol) in tetrahydrofuran (1.5 mL) was added polystrene-diisopropylethylamine resin (394 mg, 1.4 mmol) and dimethylsulfamoyl chloride (35 RL, 0.324 mmol). The reaction was mixed overnight at room temperature. Excess dimethylsulfamoyl chloride (35 IIL, 0.324 mmol) was added to the reaction to drive it to completion. To the reaction was added AP- Trisamine (232 mg, 0.972 mmol) and the reaction mixed for 6 hr at room temperature.

After filtration, the solvent was concentrated under reduced pressure. The crude material was purified using the preparative HPLC and lyophilized to give N- (1- dimethylsulfamoyl-4-phenyl-piperidin-4-ylmethyl)-2-methoxy-b enzamide 34. 5 mg (73% yield). 1H NMR (CDC13, rt): 8 ppm) 1.94-1. 99 (2 H, m), 2.01-2. 67 (2 H, m), 2.79 (6 H, s), 3.16-3. 24 (2 H, m), 3.42-3. 5 (2 H, m), 3.58 (3 H, s), 3.74 (2 H, d, J = 6. 3 Hz), 6.86 (1 H, d, J = 8. 1 Hz), 7.05 (1 H, t, J = 7. 5 Hz), 7.29-7. 46 (6 H, m), 7.59 (1 H, s), 8.18 (1 H, dd, J = 1. 7,7. 8 Hz). LCMS Rt 1.36 min, [M+1] 432.3.

EXAMPLE 17

2-Methoxy-N- [1-(2-methoxy-ethylsulfamoyl)-4-phenyl-piperidin- 4-ylmethyl]-benzamide Synthesis

Compound 1: Compound 1 is commercially available.

Compound 2: Compound 2 is commercially available.

Compound 3: Compound 3 was prepared using methodology described in Example 7 using 2-methoxy-ethylamine instead of 2,2, 2-trifluoro-ethylamine.

Compound 4: Compound 4 was as described in Example 15.

Title Compound: 2-Methoxy-N- [1- (2-methoxy-ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-benzamide was prepared using methodology described in

Example 7. lu NMR (CDC13, rt): 5 ppm) 1.95-2. 03 (2 H, m), 2.2-2. 29 (2 H, m), 3.12-3. 22 (4 H, m), 3.30 (3 H, s), 3.41-3. 48 (4 H, m), 3.58 (3 H, s), 3.73 (2 H, d, J = 6.1 Hz), 4.55 (1 H, t, J = 5. 8,11. 7 Hz), 6.86 (1 H, d, J = 8. 2 Hz), 7.04 (1 H, dt, J = 0.9, 7. 5 Hz), 7.28-7. 45 (6 H, m), 7.59 (1 H, t, J = 5. 7,8. 65 Hz), 8.17 (1 H, dd, J = 2. 0, 7.85 Hz). LCMS Rt 1.36 min, [M+1] 462.

EXAMPLES 18 TO 22 Examples 18 to 22 were prepared using methodology described in Example 17. Example Structure Name M+H 18. o o N- (l-Benzylsulfamoyl-4-phenyl- 495 piperidin-4-ylmethyl)-2-methoxy- benzamide ION O=S=O HO 19 n o o, CH3 2-Methoxy-N-(4-phenyl-1-447 propylsulfamoyl-piperidin-4-ylmethyl)- benzamide ION o=s=o OH Oi HO 20 n o CH3 N- [I- (4-Fluoro-benzylsulfamoyl)-4- 513 phenyl-piperidin-4-ylmethyl]-2-methoxy- benzamide ION o-s-o H F 21} ç oCH3 N-(l-Allylsulfamoyl-4-phenyl-piperidin-445 4-ylmethyl)-2-methoxy-benzamide QU U N o=s=o IN HN CH2 Example Structure Name M+H 22 o ( (CH, N- [I- (2-Hydroxy-ethylsulfamoyl)-4- 449 phenyl-piperidin-4-ylmethyl]-2-methoxy- benzamide N o=s=o HtL "OH EXAMPLE 23

2-Methoxy-N- [1-(2-oxo-oxazolidine-3-sulfonyl)-4-phenyl-piperidin- 4-ylmethyl]-benzamide Synthesis

Compound 1: Compound 1 was prepared as described in Example 15.

Title Compound: A solution of chlorosulfonyl isocyanate (0.12 mL; 1.4 mmol) in dichloromethane (20 mL) was cooled to 0°C and treated with 2- chloroethanol (0.094 mL; 1.3 mmol. After 2 h a solution of compound 1 (0. 42g ; 1.3 mmol) and triethylamine (0.72 mL; 5.2 mmol) in dichloromethane (15 mL) was added dropwise. When the addition was complete the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 24 h. 20% aqueous hydrochloric acid was added and the organic layer was separated, washed with

saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by column chromatography on silica gel using 9: 1 ethyl acetate: hexane as the eluent to give 0.3 g of 2-methoxy-N-[1-(2-oxo- oxazolidine-3-sulfonyl)-4-phenyl-piperidin-4-ylmethyl]-benza mide as a white solid.

LCMS m/z=475 (M+H) + EXAMPLE 24

Synthesis

Compound 1: Compound 1 is commercially available.

Compound 2: Trifluroethylamine (6.6 mg, 0.067 mmol) and compound 1 (16 mg, 0.067 mmol) were added into iPrOH (1.0 mL). The reaction mixture was heated at 95 °C for 6 h.

Compound 3: Compound 3 was prepared as described in Example 1.

Title Compound: Compound 3 (20 mg, 0.060 mmol) in acetonitrile (0.50 mL) was added to compound 2 in iPrOH.. The reaction was heated at 95 °C for 14 h and concentrated. The residue was purified through Prep HPLC to yield the title compound (4.4 mg, 15% yield) as a clear oil. HPLC Rt 3.13 min, Purity 91%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.62 min, [M+1] 480.18 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.91-1. 99 ppm, 2H, m; 2.12-2. 16 ppm, 2H, m; 3.40- 3.47 ppm, 2H, m; 3.65-3. 68 ppm, 5H, m; 3.77-3. 83 ppm, 2H, m; 3.94-3. 97 ppm, 2H, m; 5.32 ppm, 1H, m; 6.85-6. 87 ppm, 2H, m; 6.98-7. 02 ppm, 2H, m; 7.27 ppm, 1H, dd, J=5.0 Hz and 0.8 Hz; 7.35-7. 40 ppm, 1H, m; 7.82 ppm, 1H, m; 8.06- 8.09 ppm, 1H, m.

EXAMPLE 25 Scheme 1 2 3 Compound 1 : Compound 1 was prepared as described in Example 15. Compound 2: A solution of compound 1 (0.63 g; 1.9 mmol) in anhydrous acetonitrile (20 mL) was treated with diphenyl N-cyanocarbonimidate (0.95 g; 4.0

mmol) and the reaction mixture was heated to 85°C. After 19 h the acetonitrile was removed by evaporation and the residue was portioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 7: 3 ethyl acetate: hexane as the eluent gave 0.89 g of compound 2 as a white solid. LCMS ll-b/z = 470 (M+H) + Title Compound: Compound 3 (0.1 g; 0.2 mmol) was treated with 7 N ammonia in methanol (1.5 mL) and heated to 45°C in a sealed tube for 1 h. The methanol and ammonia was removed by evaporation and the residue was portioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The crude product was purified by recrystallization from ethyl acetate to give 0.064 g of the title compound as white crystals. LCMS/ = 392 (M+H) + EXAMPLES 26 TO 58 Examples 26 to 58 were prepared using methology described in Example 24 and Example 25. Example Structure Name [M+1] 26 N 519 1\/1 N I N I F N N- F nez N U zizi Zu NEZ N- L jazz fuzz nez NE ! N Example Structure Name [M+1] 29 so ol 411 \/N y N s< N N=l Ns 30 0 OrCH3 392 N-b H jan r NH2 1112 N 31 o'421 N H NUI N'CH3 ZU N 32 0 oc"3 501 I H, \ nu S N < zu J' 33 0, c"3 407 N 33 0/CH3 407 N N gXCHH3 ! CHIA N 34 a oc"3 435 2 H CH3 ACHS H N III" 35 0 cl3 449 N zizi 11, H N NNCH3 III" N Example Structure Name [M+l] 36 HOAH3 461 N \ C. N) tHNX N N ! i H 37 0 OICH3 433 Nu 0" z ; H~CH2 H N 38 o 437 \ NU OH ICI OH 'OH 39 0 oH3 447 0 N H r-v t N 40 o'431 1 -b N N H'-"% CH Ici N 41 0cl3 515 N N NJN F H N 42 0 "3 447 Hz NEZ N I L/I Nô N Example Structure Name [M+l] 43 T N 463 N H N T N) I" 10 44 ° 0°"3 435 C) N t ; N~CH3 ici H NON 45 FHNXa 439 N H I/ N N NeN-trCH3 CHs '46 o o 465 Nez H N N N"N'-O'CH III lH3 N 47 1 0 426 N H N F NNCH3 N H 48 XN X 426 Nu- HF I NIF INCH, H N 49 N0ol CH3 421 H)-a QU U '11' NN-CHs N N 50 0 408 w N w F H N N''NCH3 1t H N Example Structure Name [M+l] 51 ru) P 391 N i N #N^CH3 il" N 52/ o o. cH3 484 NEZ "I/ N N N\N H t 53 0 o o" 460 NEZ zizi N-CN N CHAN 54 0 0 Cl 495 EDCI 0" N N"N'CH3 zu N 55 IF 511 54 o CI 495 N Y N all Ici" N Q H U I Hz N' t N^CH3 fil N 57 o"go F 463 Nui H F N 11, H3 N CL3 58 10, 00 487 NH 0"Y' NU3 II H H N EXAMPLE 59

Synthesis s S S w --N NHBOC 1) chloroethylll NHBoc 1) LAH, THF chloroformate N N N 0, TEA 2) MEOH H 3 0 DCM 10 p e 1 2 4-Fluoro-benzenesulfonyl N chloride TEA, DCM NHBoe cyclohexyl amine H H-0 H cyclohexyl amine lue O=S=o PrOH i'O=S=O O=S=O 2) Compound 32 /iPrOH 6 5 4 \ 6 I 5 4 \ F F F

Compound 1: Compound 1 was prepared as described in Example 1.

Compound 2: To a solution of compound 1 (3.5 g, 12 mmol) in dry THF (70 mL) was added LAH (35 mL, 35 mmol, 1. OM solution in tetrahydrofuran). The reaction mixture was heated to reflux for 1.5 h then allowed to cool to ambient temperature. The solution was cooled to 0 °C and quenched with water (9.2 mL), 1N NaOH (5.8 mL) and water (9.2 mL). The quenched reaction mixture was stirred at

ambient temperature for 0.5 h. The slurry was filtered through a celite pad and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL), washed with saturated NaHC03 (2 x 100 mL), dried over MgS04, filtered and concentrated to give a brown oil. This residue was dissolved in dichloromethane (75 mL) and carbonic acid di-tert-butyl ester (2.9 g, 13 mmol) and TEA (1.8 mL, 13 mmol) were added subsequently. The reaction mixture was stirred at ambient temperature for 18 h and then concentrated. The product compound 2 was purified by flash silica gel chromatography elution with 2: 1 hexane: ethylacetate (3.5g, 75% yield for two steps).

HPLC Rt 2.44 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.39 min, [M+1] 387.24 Phenomenex S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.32 ppm, 9H, s; 1.80 ppm, 2H, m; 1.96 ppm, 2H, m; 2.22 ppm, 2H, m; 2.55-2. 58 ppm, 2H, m; 3. 21 ppm, 2H, d, J = 6. 3 Hz ; 3. 35 ppm, 2H, s; 4. 30 ppm, 1H, m; 6. 76 ppm, 1H, dd, J = 0.8 Hz and 3.4 Hz; 6.90-6. 91 ppm, 1H, m; 7.13-7. 21 ppm, 6H, m.

Compound 3: Compound 2 (1.7 g, 4.5 mmol) was dissolved in dichloroethane (35 mL) and TEA (3.1 mL, 22.4 mmol) was added. At 0 °C chloroethyl chloroformate (0.97 mL, 8.9 mmol) in dichloroethane (17 mL) was added.

The reaction mixture was stirred at ambient temperature for 1 h, then another 1.0 mL chloroethyl chloroformate and 3.0 mL TEA were added. The reaction mixture was stirred at ambient temperature for a further 2h then concentrated and dried under high vacuum for 0.5 h. MeOH (20 mL) was added to the residue and was heated to reflux for 4 h. The reaction mixture was concentrated and the residue was taken directly to the next step.

Compound 4: Compound 3 was dissolved in dichloromethane (60 mL). At ambient temperature TEA (1.9 mL, 13.4 mmol) was added followed by the addition of 4-Fluoro-benzenesulfonyl chloride (1.0 g, 5.4 mmol). The reaction mixture was stirred for 18 h and then concentrated. Compound 4 (1.44 g, 71% yield) was isolated as a white solid by column chromatography using 2: 1 Hexane: EtOAc. HPLC Rt 3.56 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.82 min, [M+23]

477.13 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.32 ppm, 9H, s; 1.86- 1.88 ppm, 2H, m; 2.03-2. 06 ppm, 2H, m; 2.70-2. 74 ppm, 2H, m; 3.13 ppm, 2H, d, J = 6.6 Hz; 3.40-3. 42 ppm, 2H, m; 4.30 ppm, 1H, m; 6.70 ppm, 1H, d, J = 3.3 Hz; 6.87-6. 89 ppm, 1H, m; 7.07-7. 10 ppm, 1H, m; 7.13-7. 14 ppm, 1H, m; 7.65- 7.68 ppm, 2H, m.

Compound 5: Compound 4 (55 mg, 0.12 mmol) was dissolved in dichloromethane (1.3 mL). To this solution TFA (180 gel, 2.3 mmol) in dichloromethane (0.50 mL) was added and the reaction was stirred at ambient temperature till no starting material was detected according to LC-MS. The reaction mixture was concentrated and neutralized with TEA. To the concentrated residue was added diphenyl cyanocarbonimidate (32 mg, 0.13 mmol) and isopropyl alcohol (1.0 mL). The reaction mixture was heated to reflux for 18 h.

Title Compound: Cyclohexyl amine (19 mg, 0.19 mmol) was added to compound 5 and the reaction was heated at 95 °C for 24h. The reaction mixture was concentrated and purified by Prep-HPLC YMC ODS S5 20x100mm, 16 min gradient 40 to 100% MeOH (90% in water 0. 1% TFA) at 20mL/min UV detection at 220nM to give the title compound as a yellow oil (23.8 mg, 39% yield). HPLC Rt 3.49 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.81 min, [M+1] 504.24 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220nm. NMR H (CDCl3) 1. 01-1. 24 ppm, 5H, m; 1.56-1. 58 ppm, 1H, m; 1.66-1. 77 ppm, 4H, m; 1.91-1. 94 ppm, 2H, m; 2.15-2. 18 ppm, 2H, m; 2.75-2. 79 ppm, 2H, m; 2.98-3. 01 ppm, 1H, m; 3.27 ppm, 2H, d, J = 6.1 Hz; 3.45-3. 47 ppm, 2H, m; 6.81 ppm, 1H, dd, J = 3.9 Hz and 1.1 Hz; 6.98 ppm, 1H, dd, J = 3. 3 Hz and 4. 9 Hz ; 7.13-7. 19 ppm, 2H, m; 7.25-7. 29 ppm, 1H, m; 7.71-7. 76 ppm, 2H, m.

EXAMPLES 60 TO 63 Examples 60 to 63 were prepared as described in Example 59. Example Structure Name [M+ll 60 N 435 Nui s non C N i O=S=O \ N 61 1 477 1 N " 0=S=0 i ofo 62 M 541 nain NON i O=S=O 0=S=0 N 63 F Ny 505 N) ion O=S=O 'N 0=S=0 O=S=O F EXAMPLE 64

Synthesis s 0 0 S 11 NHBoc 1) TFA, DCM N 11 N 0 i H 0 2 2) Chlorosulfonyl N o=S=o isocyanate, chloroethanol, TEA, DCM 2 O F 0 F F S O NS\N / vs cyclohexyl amine N , I TEA, ACON F

Compound 1: Compound 1 was prepared using methodology described in Example 59.

Compound 2: To the solution of compound 1 (500 mg, 1.1 mmol) in dichloromethane (5.0 mL) was added TFA (3.0 mL) in dichloromethane (12 mL) and the reaction was stirred for 1.5 h. Then the mixture was concentrated and neutralized with TEA. At 0 °C 2-chloroethanol (74 I1L, 1.1 mmol) in dichlormethane (7.5 mL)

was added to the solutions of chlorosulfonyl isocyanate (96 u. L, 1.1 mmol) in dichloromethane (7.5 I1L). The reaction mixture was stirred at 0 °C for 1 h. The crude amine in dichloromethane (5.0 mL) and TEA (460 uL, 3.3 mmol) were added.

The reaction was stirred for 18 h and concentrated. Compound 2 (260 mg, 47% yield) was purified as a white solid by column chromatography using 1: 1 Hexane: EtOAc.

HPLC Rt 2.86 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.48 min, [M+1] 504.08 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.86-1. 96 ppm, 2H, m; 2.14-2. 17 ppm, 2H, m; 2.56-2. 62 ppm, 2H, m; 3.07 ppm, 2H, d, J = 6. 9 Hz ; 3.51-3. 53 ppm, 2H, m; 3. 90 ppm, 2H, t, J = 7. 8 Hz ; 4. 32 ppm, 2H, t, J = 7. 8 Hz; 5. 17 ppm, 1H, t, J= 6. 9 Hz ; 6. 75 ppm, 1H, d, J = 3. 4 Hz ; 6.88-6. 90 ppm, 1H, m; 7.07-7. 09 ppm, 2H, m; 7. 11-7. 18 ppm, 1H, m; 7.63-7. 67 ppm, 2H, m.

Title Compound: Cyclohexyl amine (7.7 mg, 0.078 mmol), TEA (130 gel) and compound 2 (26 mg, 0.052 mmol) were dissolved in acetonitrile (1.0 mL). The reaction was heated at 85 °C for 18 h and concentrated. The title compound was purified as an orange oil (24.1 mg, 90% yield) by Prep-HPLC YMC ODS S5 20x100mm, 16 min gradient 40 to 100% MeOH (90% in water 0. 1% TFA) at 20mL/min UV detection at 220nM. HPLC Rt 3.51 min, Purity 100%, YMC S5 column 4.6 x 50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% PPA) UV detection at 220nm. LCMS Rt 1.82 min, [M+1] 516.16 YMC S5 column 4.6 x 30 mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220nm. NMR H (CDC13) 1.05-1. 11 ppm, 3H, m; 1.16-1. 21 ppm, 2H, m; 1.49- 1.51 ppm, 1H, m; 1.59-1. 63 ppm, 2H, m; 1.77-1. 80 ppm, 2H, m; 1.88-1. 92 ppm, 2H, m; 2.15-2. 18 ppm, 2H, m; 2.62-2. 68 ppm, 2H, m; 2.94-2. 98 ppm, 3H, m; 3.43-3. 45 ppm, 2H, m; 3.84 ppm, 1H, m; 6.73-6. 74 ppm, 1H, m; 6.88-6. 89 ppm, 1H, m; 7. 01-7. 11 ppm, 2H, m; 7.17 ppm, 1H, dd, J = 1.1 Hz and 5.5 Hz; 7.65-7. 67 ppm, 2H, m.

EXAMPLES 65 TO 73 Examples 65 to 73 were prepared using methodology described in Example 64. Example Structure Name [M+1] 65 s ° 447 N-SIN- N I O=S=O F 66 s 101 489 F O=S=O 0=S=0 F 67 s lot F F 515 N-SSN-- I JN i oxo i \ 4=0 68 s lot 487 NON V OXO i o=s=o 539 non PO N i o=s=o i 70 tN ò NJ 3 509 , S"o N bon N F " o=s=o Example Structure Name [M+l] 71 s 0'-0 71 S ° 553 F '' N O=S=O O=S=O O 72 F 72 s 101 523 N zu O=S=O T o=s=o N. o Vo 503 N F i F EXAMPLE 74

4-benzylcarbamoyl-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester Synthesis

1 2 Compound 1: Compound 1 is commercially available.

Compound 2: A solution of compound 1 (12.6 g; 33.4 mmol) in 100 mL of 1 N sodium hydroxide and 25 mL of tetrahydrofuran was treated with di-tert-butyl

dicarbonate (10.3g ; 47.2 mmol) at room temperature. After stirring for 20 h, 10% aqueous hydrochloric acid was slowly added to neutralize the reaction mixture to pH = 7. Ethyl acetate (approximately 300 mL) was added and the organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give compound 2 as a white solid (10.2 g) that was used without further purification. LCMS 77z/Z= 306 (M+H) + Title Compound: A solution of compound 2 (0.92 g; 3.0 mmol) in tetrahydrofuran (30 mL) was treated with benzotriazol-l- yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.77 g; 4.0 mmol) and triethylamine (0.63 mL; 4.5 mmol) at room temperature. The reaction mixture was allowed to stir for 0.5 h at which time benzyl amine (0.39 mL; 3.6 mmol) was added and the reaction mixture was heated to 45°C for 2 h. The tetrahydrofuran was removed by evaporation and the residue was treated with ethyl acetate (approximately 150 mL) and 5% aqueous hydrochloric acid (approximately 100 mL). The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 7: 3 hexane: ethyl acetate as the eluent gave 0.93 g of 4-benzylcarbamoyl-4-phenyl- piperidine-l-carboxylic acid tert-butyl ester as a white solid. LCMS 7X/Z= 396 (M+H) + EXAMPLES 75 TO 84 Examples 75 to 84 were prepared as described in Example 74. Example Structure Name M+H 75 CH3 4-(2-Methoxy-benzylcarbamoyl)-4-425 phenyl-piperidine-1-carboxylic acid N tert-butyl ester H o-o 76-CH3 4- [2- (4-Methoxy-phenyl)- 439 W ethylcarbamoyl]-4-phenyl-piperidine- CGH l-carboxylic acid tert-butyl ester N 0A0k 77 CH3 4-(2, 4-Dimethoxy-benzylcarbamoyl)-455 0 4-phenyl-piperidine-1-carboxylic acid test-butyl ester N oi 78 Cl 4- [2- (2, 6-Dichloro-phenyl)- 478 /o-oi ethylcarbamoyl]-4-phenyl-piperidine- 1-carboxylic acid tert-butyl ester H ozon 79 0" 4-Phenyl-4- (3-phenyl- 423 N propylcarbamoyl)-piperidine-l- H carboxylic acid tert-butyl ester N 0A0k 80 CH3 4-Pentylcarbamoyl-4-phenyl-375 X XN//~ piperidine-l-carboxylic acid tert-butyl ester % H OZON oo< Example Structure Name M+H 81 CHs 4- (3-Methoxy-propylcarbamoyl)-4- 377 phenyl-piperidine-l-carboxylic acid N tert-butyl ester H 0 82 /o 0 4- (4-Methoxy-benzylcarbamoyl)-4- 425 phenyl-piperidine-1-carboxylic acid tert-butyl ester N o 83 F 4- (3, 4-Difluoro-benzylcarbamoyl)-4- 431 0 F phenyl-piperidine-l-carboxylic acid N tert-butyl ester H 00 84 0 4- (4-Fluoro-benzylcarbainoyl)-4- 413 Q N phenyl-piperidine-l-carboxylic acid tert-butyl ester N 00 EXAMPLE 85

4-phenyl-piperidine-4-carboxylic acid benzylamide Synthesis

Compound 1: Compound 1 was prepared as described in Example 74.

Title Compound: A solution of compound 1 (0.93 g; 2.4 mmol) in 30 mL of dichloromethane was treated with 4 mL trifluroacetic acid at room temperature. After stirring for 20 h, an additional 100 mL of dichloromethane was added followed by 100 mL 1 N sodium hydroxide. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give 0.67 g of 4-phenyl-piperidine-4-carboxylic acid benzylamide as a colorless oil that was used without further purification. LCMS m/z = 295 (M+H) + EXAMPLES 86 TO 93 Examples 86 to 93 were prepared as described in Example 85. Example Structure Name M+H 86 4-Phenyl-piperidine-4-carboxylic acid 355 0 2, 4-dimethoxy-benzylamide 'C H, H 3 H H 87 n ° (4-Phenyl-piperazin-l-yl)-(4-phenyl-350 eridin-4-yl)-methanone In N H 88 o"'4-Phenyl-piperidine-4-carboxylicacid 325 2-methoxy-benzylamide 'N H N H 89 0 4-Phenyl-piperidine-4-carboxylic acid 325 N CHs H 4-methoxy-benzylamide N H 90/°" 4-Phenyl-piperidine-4-carboxylic acid 339 [2- (4-methoxy-phenyl)-ethyl]-amide zon NAH H H 91' 4-Phenyl-piperidine-4-carboxylic acid 323 -N (3-phenyl-propyl)-amide H N H Example Structure Name M+H 92 0 CH3 4-Phenyl-piperidine-4-carboxylic acid 275 pentylamide ZON H 93 0 _C (CH 4-Phenyl-piperidine-4-carboxylic acid 277 <-N (3-methoxy-propyl)-amide N H EXAMPLE 94

4-Phenyl-1-(2-phenyl-cyclopropanecarbonyl)-piperidine- 4-carboxylic acid benzylamide Synthesis

1 2 Compound 1: Compound 1 was prepared as described in Example 85.

Title Compound: Compound 1 (0.015 g; 0.05 mmol) was dissolved in 1 mL acetonitrile. Polystyrene-diisopropylethylamine (PS-DIEA) resin (0. lg) was added and the resulting suspension was treated with trans-2-phenyl-cyclopropanecarbonyl chloride (0.02 g; 0.1 mmol) and shaken at room temperature. After 21 h, polystyrene-

triamine (PS-trisamine) resin (0.1 g) was added and the reaction mixture was allowed to shake an additional 24 h. The reaction mixture was filtered and concentrated to give 0.015 g of 4-phenyl-1- (2-phenyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid benzylamide as a colorless oil. LCMS m/z = 440 (M+H) +.

EXAMPLE 95

1- (3-Fluoro-benzenesulfonyl)-4-phenyl-piperidine-4-carboxylic acid benzylamide Synthesis n OX F, ¢, SO2CI Q NX a IPS-DIEA, MECN 00H N N H 2. PS-trisamine oSSF Ou 1 ; 1

Compound 1: Compound 1 was prepared as described in Example 85.

Title Compound: Compound 1 (0.015 g; 0.05 mmol) was dissolved in 1 mL anhydrous acetonitrile. Polystyrene-diisopropylethylamine (PS-DIEA) resin (0. lg) was added and the resulting suspension was treated 3-fluoro-benzenesulfonyl chloride (0.02 g; 0.1 mmol) and shaken at room temperature. After 21 h, polystyrene- trisamine (PS-trisamine) resin (0.1 g) was added and the reaction mixture was allowed to shake an additional 24 h. The reaction mixture was filtered and concentrated to give 0.012 g of 1- (3-fluoro-benzenesulfonyl)-4-phenyl-piperidine-4-carboxylic acid benzylamide as a colorless oil. LCMS = 454 (M+H) + EXAMPLE 96

4-Benzylcarbamoyl-4-phenyl-piperidine-1-carboxylic acid ethyl ester Synthesis 1 Compound 1: Compound 1 was prepared as described in Example 85.

Title Compound: 4-Benzylcarbamoyl-4-phenyl-piperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. LCMS n ? lz = 367 (M+H) + EXAMPLES 97 TO 269 Examples 97 to 269 were synthesized using methodology described in Example 94, Example 95 and Example 96. Example Structure Name M+H 0 4-phenyl-l- (2-phenyl- 500 cyclopropanecarbonyl)-piperidine- N 4-carboxylic acid 2, 4-dimethoxy- H benzylamide N O k 98 o l- (4-Methoxy-benzoyl)-4-phenyl- 490 <, cHs plperidine-4-carboxylic acid2, 4- dimethoxy-benzylamide N ° I \ /CH3 99 (CH3 1- [2- (4-Fluoro-phenyl)-acetyl]-4- 492 phenyl-piperidine-4-carboxylic acid 2, 4-dimethoxy-benzylamide F N I 100, °"3 1- [2- (3-Methoxy-phenyl)-acetyl]- 504 ^</CH3 4-phenyl-piperidine-4-carboxylic "acid 2, 4-dimethoxy-benzylamide J wCHa O \ OcHa 101 1-[2-(4-Chloro-phenoxy)-acetyl]-4-524 phenyl-piperidine-4-carboxylic acid 2, 4-dimethoxy-benzylamide N O 102 1- (3-Cyclopentyl-propionyl)-4- 480 phenyl-piperidine-4-carboxylic acid 2, 4-dimethoxy-benzylamide < 103 CHa 1-Butyryl-4-phenyl-piperidine-4-426 carboxylic acid 2, 4-dimethoxy- benzylamide N O 'CH3 Example Structure Name M+H 104 dcH 1- (2-Fluoro-benzoyl)-4-phenyl- 479 \- CH3 piperidine-4-carboxylic acid 2, 4- dimethoxy-benzylamide N F 105 t-Cyclohexanecarbonyl-4-phenyl-466 (. H3 piperidine-4-carboxylic acid 2, 4- dimethoxy-benzylamide 0 106 o (2-Phenyl-cyclopropyl)- [4-phenyl- 495 4- (4-phenyl-piperazine-l- carbonyl)-piperidin-1-yl]- methanone ° I kj 107' ° [1- (4-Methoxy-benzoyl)-4-phenyl- 485 piperidin-4-yl]- (4-phenyl- piperazin-1-yl)-methanone 0 ; p wo, CH3 108 0 2- (4-Fluoro-phenyl)-l- [4-phenyl-4- 487 ( (4-phenyl-piperazine-1-carbonyl)- piperidin-1-yl]-ethanone N F 1 au oj_-o-F 109 n 2- (3-Methoxy-phenyl)-1- [4- 499 N--/phenyl-4- (4-phenyl-piperazine-l- carbonyl)-piperidin-1-yl]-ethanone CL3 O \ I OiCHa 110 0 2- (4-Chloro-phenoxy)-l- [4-phenyl- 519 4- (4-phenyl-piperazine-l- carbonyl)-piperidin-1-yl]-ethanone N O\ WCI I ill 3-Cyclopentyl-l- [4-phenyl-4- (4- 475 N/--N phenyl-piperazine-l-carbonyl)- piperidin-1-yl]-propan-1-one N o<) Example Structure Name M+H 112' 0 1- [4-Phenyl-4- (4-phenyl- 421 piperazine-1-carbonyl)-piperidin-I- yl]-butan-l-one 1 OJ<CH3 113' ° (2-Fluoro-phenyl)- [4-phenyl-4- (4- 473 phenyl-piperazine-1-carbonyl)- N piperidin-1-yl]-methanone °91 F F 114- o (1-Cyclohexanecarbonyl-4-phenyl-461 piperidin-4-yl)- (4-phenyl- piperazin-1-yl)-methanone N 0--l-0 115 0 4-Phenyl-l- (2-phenyl- 470 cyclopropanecarbonyl)-piperidine- 4-carboxylic acid 4-methoxy- benzylamide 116 0 1- (4-Methoxy-benzoyl)-4-phenyl- 460 vNCOCH3 piperidine-4-carboxylic acid 4- "methoxy-benzylamide N Cl3 I/iCHa O 117 0 1- [2- (4-Fluoro-phenyl)-acetyl]-4- 462 N phenyl-piperidine-4-carboxylic H acid 4-methoxy-benzylamide F N 118 0 1- [2- (3-Methoxy-phenyl)-acetyl]- 474 N H3 4-phenyl-piperidine-4-carboxylic "acid 4-methoxy-benzylamide Son n O \ I OiCHa 119 0 1- [2- (4-Chloro-phenoxy)-acetyll-4- 494 N , cH3 phenyl-piperidine-4-carboxylic SN) acid 4-methoxy-benzylamide N 9\CI I CI Example Structure Name M+H 120 0 1- (3-Cyclopentyl-propionyl)-4- 450 N ', cH3 phenyl-piperidine-4-carboxylic r""acid 4-methoxy-benzylamide N Jan O' v Y \ 121 f) o 1-Butyryl-4-phenyl-piperidine-4-396 N/-/C (CH3 carboxylic acid 4-methoxy- H o benzylamide N o) CH3 122/° ° 1-(2-Fluoro-benzoyl)-4-phenyl-448 vH/-ao&H3 piperidine-4-carboxylic acid 4- "methoxy-benzylamide N j0 FUZZ 123/o 1-Cyclohexanecarbonyl-4-phenyl-436 N/__ H3 piperidine-4-carboxylic acid 4- H methoxy-benzylamide N 0 124 4-Phenyl-l- (2-phenyl- 470 o \ cyclopropanecarbonyl)-piperidine- N 4-carboxylic acid 2-methoxy- tNX benzylamide N 125 0/cl3 1- (4-Methoxy-benzoyl)-4-phenyl- 460 o piperidine-4-carboxylic acid 2- N methoxy-benzylamide H N O \ 0 Example Structure Name M+H 126 O/CH, 1- [2- (4-Fluoro-phenyl)-acetyl]-4- 462 n o phenyl-piperidine-4-carboxylic nib acid 2-methoxy-benzylamide H F N 1 127 l- [2- (3-Methoxy-phenyl)-acetyl]- 474 o 4-phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide "fuzz ooc 128 vCH3 1- [2-(4-Chloro-phenoxy)-acetyl]-4-494 /Hz phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide NEZ N O I ci 129 zCH3 1- (3-Cyclopentyl-propionyl)-4- 450 phenyl-piperidine-4-carboxylic acid 2-methoxy-benzylamide N J O' 130, CH3 1-Butyryl-4-phenyl-piperidine-4-396 carboxylic acid 2-methoxy- N benzylamide C" N O''C"3 131 oXCH3 1- (2-Fluoro-benzoyl)-4-phenyl- 448 n o < piperidine-4-carboxylic acid 2- N methoxy-benzylamide H zu F ExampleStructureNameM+H 132 ZCH3 1-Cyclohexanecarbonyl-4-phenyl-436 o \ piperidine-4-carboxylic acid 2- N methoxy-benzylamide Zu H O' 133/ o l- (4-Methoxy-benzoyl)-4-phenyl- 440 /-U piperidine-4-carboxylic acid < benzylamide N CL3 I/iCHa O 134 1- [2- (4-Fluoro-phenyl)-acetyl]-4- 430 N phenyl-piperidine-4-carboxylic "acid benzylamide F N 1 135 0 1- [2- (3-Methoxy-phenyl)-acetyl]- 444 neo 4-phenyl-piperidine-4-carboxylic "'acid benzylamide n I OIICH3 136 0 1- [2- (4-Chloro-phenoxy)-acetyl]-4- 464 N , phenyl-piperidine-4-carboxylic "acid benzylamide N zozo O v'CI 137 0 1- (3-Cyclopentyl-propionyl)-4- 420 N phenyl-piperidine-4-carboxylic "acid benzylamide N N 138/o 1-Butyryl-4-phenyl-piperidine-4-365 Nez carboxylic acid benzylamide "I N oXCH3 Example Structure Name M+H 139/° ° 1-(2-Fluoro-benzoyl)-4-phenyl-417 N piperidine-4-carboxylic acid "benzylamide N Fez F I 140 rß ° l-Cyclohexanecarbonyl-4-phenyl-406 N/__o piperidine-4-carboxylic acid "benzylamide N zu 141 O/cH3 4-Phenyl-1-(2-phenyl-422 n °\\} cyclopropanecarbonyl)-piperidine- N 4-carboxylic acid (3-methoxy- "propyl)-amide N O 142 0 0"3 1- (4-Methoxy-benzoyl)-4-phenyl- 412 piperidine-4-carboxylic acid (3- N methoxy-propyl)-amide H N /tich3 CHs 143 zCH3 1-[2-(4-Fluoro-phenyl)-acetyl]-4-414 °) °u phenyl-piperidine-4-carboxylic N acid (3-methoxy-propyl)-amide H if N 1 144 o/CH3 1-[2-(3-Methoxy-phenyl)-acetyl]-426 g) \oX,} 4-phenyl-piperidine-4-carboxylic N' acid (3-methoxy-propyl)-amide H N oae CH3 Example Structure Name M+H 145, CH3 1- [2-(4-Chloro-phenoxy)-acetyl]-4-446 rß o) phenyl-piperidine-4-carboxylic N acid (3-methoxy-propyl)-amide H C. N c. 146 CH3 1-(3-Cyclopentyl-propionyl)-4-402 C ) °) phenyl-piperidine-4-carboxylic N acid (3-methoxy-propyl)-amide H N C- 147 o&H3 1-Butyryl-4-phenyl-piperidine-4-347 n o > carboxylic acid (3-methoxy- N propyl)-amide H N O'v'CH, 148 ZCH3 1-(2-Fluoro-benzoyl)-4-phenyl-399 /°) o ~) piperidine-4-carboxylic acid (3- N methoxy-propyl)-amide H N F F/II 149 oCH3 1-Cyclohexanecarbonyl-4-phenyl-388 /o) piperidine-4-carboxylic acid (3- N methoxy-propyl)-amide H N 150 O-CH3 4-Phenyl-l- (2-phenyl- 484 0 cyclopropanecarbonyl)-piperidine- N 4-carboxylic acid [2- (4-methoxy- H phenyl)-ethyl]-amide zu 0 Example Structure Name M+H 151 A °w"3 1- (4-Methoxy-benzoyl)-4-phenyl- 474 piperidine-4-carboxylic acid [2- (4- W,-o methoxy-phenyl)-ethyl]-amide H Ola O /% H 152 °°"3 1- [2- (4-Fluoro-phenyl)-acetyl]-4- 476 0 phenyl-piperidine-4-carboxylic t4 acid [2- (4-methoxy-phenyl)-ethyll- "amide F N I O 153 O-CH3 1- [2- (3-Methoxy-phenyl)-acetyll- 488 4-phenyl-piperidine-4-carboxylic N acid [2- (4-methoxy-phenyl)-ethyll- "amide Nul °iC"3 154 | wO-CH3 1-[2-(4-Chlpro-phenoxy)-acetyl]-4-508 X phenyl-piperidine-4-carboxylic N acid [2- (4-methoxy-phenyl)-ethyl]- "amide N ho o i 155 O-CH3 1- (3-Cyclopentyl-propionyl)-4- 464 o\ t ß phenyl-piperidine-4-carboxylic N acid [2- (4-methoxy-phenyl)-ethyl]- "amide N O' 156 gO-CH3 1-Butyryl-4-phenyl-piperidine-4-410 t\ \ S carboxylic acid [2- (4-methoxy- N phenyl)-ethyl]-amide H N 0-CH, Example Structure Name M+H 157 °-cH3 1- (2-Fluoro-benzoyl)-4-phenyl- 462 n o X piperidine-4-carboxylic acid [2- (4- N methoxy-phenyl)-ethyl]-aniide H N Oo 158 HO-CH3 1-Cyclohexanecarbonyl-4-phenyl-450 0 piperidine-4-carboxylic acid [2- (4- X H methoxy-phenyl)-ethyl]-amide H N 159 4-Phenyl-l- (2-phenyl- 468 cyclopropanecarbonyl)-piperidine- 0 4-carboxylic acid (3-phenyl- N propyl)-amide H N < H O Y 160 1- (4-Methoxy-benzoyl)-4-phenyl- 458 piperidine-4-carboxylic acid (3- o phenyl-propyl)-amide \ N N H ou 9H 161 \ 1- [2-(4-Fluoro-phenyl)-acetyl]-4-460 phenyl-piperidine-4-carboxylic o acid (3-phenyl-propyl)-amide N H 0\H c N F O Example Structure Name M+H 162 1- [2- (3-Methoxy-phenyl)-acetyl]- 472 4-phenyl-piperidine-4-carboxylic 0 acid (3-phenyl-propyl)-amide N H N/ O \ I OiCHs 163 1- [2- (4-Chloro-phenoxy)-acetyll-4- 492 phenyl-piperidine-4-carboxylic XNX acid (3-phenyl-propyl)-amide N H N ho Gi 164 1- (3-Cyclopentyl-propionyl)-4- 448 phenyl-piperidine-4-carboxylic xi acid (3-phenyl-propyl)-amide N H N O' v 165 1-Butyryl-4-phenyl-piperidine-4-394 carboxylic acid (3-phenyl-propyl)- 0 amide N H N Y O-CHs 166 1- (2-Fluoro-benzoyl)-4-phenyl- 446 piperidine-4-carboxylic acid (3- phenyl-propyl)-amide N H o F N Example Structure Name M+H 167 1-Cyclohexanecarbonyl-4-phenyl-434 piperidine-4-carboxylic acid (3- o phenyl-propyl)-amide H N N ihn 168 " l-But-2-enoyl-4-phenyl-piperidine-424 o H3 4-carboxylic acid 2, 4-dimethoxy- N benzylarnide I N O'vi'CH3 169 " CH3 (3-Fluoro-benzenesulfonyl)-4- 514 0 pheiiyl-piperidine-4-carboxylic \ N \, oac"3 acid 2, 4-dimethoxy-benzylamide H N F o \ / F 170 0 1- [4-Phenyl-4- (4-phenyl- 419 piperazine-1-carbonyl)-piperidin-1- yl]-but-2-en-l-one N O4CH3 171/\ o [l- (3-Fluoro-benzenesulfonyl)-4- 509 phenyl-piperidin-4-yl]- (4-phenyl- piperazin-1-yl)-methanone N N N og F F 172 g) o"1-But-2-enoyl-4-phenyl-piperidine-394 vHCOzCH3 4-carboxylic acid 4-methoxy- tNX benZylamide N O'iCH3 Example Structure Name M+H 173 0 1- (3-Fluoro-benzenesulfonyl)-4- 484 N H3 phenyl-piperidine-4-carboxylic C acid 4-methoxy-benzylamide N o, s oui I y F 174, CH3 1-But-2-enoyl-4-phenyl-piperidine-394 /% ou 4-carboxylic acid 2-methoxy- N benzylamide H N O-) CH3 175 oaCH3 1- (3-Fluoro-benzenesulfonyl)-4- 484 0 phenyl-piperidine-4-carboxylic N acid 2-methoxy-benzylamide H N H ou F 176 0 I-But-2-enoyl-4-phenyl-piperidine-363 vH/X 4-carboxylic acid benzylamide H cl O'i'CH3 177 CH3 1-But-2-enoyl-4-phenyl-piperidine-345 < o 5 4-carboxylic acid (3-methoxy- N propyl)-amide H N O'vi'CH3 178 oxCH3 1- (3-Fluoro-benzenesulfonyl)-4- 436 n °\\) phenyl-piperidine-4-carboxylic N acid (3-methoxy-propyl)-amide H N ces ou F Example Structure Name M+H 179 O-CH3 1-But-2-enoyl-4-phenyl-piperidine-408 4-carboxylic acid [2- (4-methoxy- N phenyl)-ethyll-amide H N 0<-CH, 180 O-CH3 1- (3-Fluoro-benzenesulfonyl)-4- 498 phenyl-piperidine-4-carboxylic N acid [2- (4-methoxy-phenyl)-ethyl]- H amide N 0--i F F 181 1-But-2-enoyl-4-phenyl-piperidine-392 4-carboxylic acid (3-phenyl- o propyl)-amide N H N o64 CH3 182 1- (3-Fluoro-benzenesulfonyl)-4- 482 phenyl-piperidine-4-carboxylic o acid (3-phenyl-propyl)-amide N H N 0kAX F F F 183 0 4-Benzylcarbamoyl-4-phenyl-430 piperidine-1-carboxylic acid benzyl S) ester N 'o 184/o\ » O 4-Phenyl-piperidine-1, 4-443 dicarboxylic acid 4-benzylamide 1- " [ (l-phenyl-ethyl)-amide] N CH, H W "u Example Structure Name M+H 185/t o 1-(4-Ethyl-benzenesulfonyl)-4-464 N phenyl-piperidine-4-carboxylic H acid benzylamide N ou CH3 186 1° ° 4-Phenyl-1-(thiophene-2-sulfonyl)-442 N piperidine-4-carboxylic acid H benzylamide N N 187/o 1-(3-Cyano-benzenesulfonyl)-4-461 N phenyl-piperidine-4-carboxylic H acid benzylamide N os 0 N 188 o o 1- (2-Fluoro-benzenesulfonyl)-4- 454 phenyl-piperidine-4-carboxylic H acid benzylamide _ o, t Ou __S 189 0 1- (4-Fluoro-benzenesulfonyl)-4- 454 phenyl-piperidine-4-carboxylic acid benzylamide N ou F 190 1° ° l-(4-Methoxy-benzenesulfonyl)-4-466 vN/< phenyl-piperidine-4-carboxylic H acid benzylamide N O in pus , CH3 r Example Structure Name M+H 191 0 4-Phenyl-1- (toluene-3-sulfonyl)- 450 piperidine-4-carboxylic acid X benzylamide N I 0-1 CH3 192 o 1- (2-Phenoxy-acetyl)-4-phenyl- 430 N piperidine-4-carboxylic acid C benzylamide N w O 193 0 1- (2-Phenoxy-acetyl)-4-phenyl- 458 < SN W piperidine-4-carboxylic acid (3- C phenyl-propyl)-amide N O \ O 194 c F 4- (3, 4-Difluoro-benzylcarbamoyl)- 466 H/-F 4-phenyl-piperidine-l-carboxylic acid benzyl ester N 195 0 IF 1- (2-Phenoxy-acetyl)-4-phenyl- 466 N F piperidine-4-carboxylic acid 3, 4- difluoro-benzylamide N O \ 0,, c 196 F 1- (4-Fluoro-benzenesulfonyl)-4- 490 N phenyi-piperidine-4-carboxylic acid 3, 4-difluoro-benzylamide N F o ! Example Structure Name M+H 197 0 F 4-Phenyl-piperidine-1, 4- 465 N F dicarbo'xylic acid 1-benzylamide 4- t (3, 4-difluoro-benzylamide) N pN I \ H H [J 198 0 4-Phenyl-l- (3-phenyl-acryloyl)- 462 piperidine-4-carboxylic acid 3, 4- tN) difluoro-benzylamide N p % I \ 199 fß o F 4-Phenyl-l-phenylacetyl-450 H/-F piperidine-4-carboxylic acid 3, 4- difluoro-benzylamide N J 200 rß O F l-Benzoyl-4-phenyl-piperidine-4-435 N carboxylic acid 3, 4-difluoro- benzylamide N 0--l-C 201 rß O F 4-Phenyl-l-propionyl-piperidine-4-387 '9Hz F carboxylic acid 3, 4-difluoro- benzylamide N OCH, O 202 0 F 1- (2-Benzyloxy-acetyl)-4-phenyl- 480 N/-F piperidine-4-carboxylic acid 3, 4- difluoro-benzylamide N o 203 4- (l-Benzyl-pyrrolidin-3- 499 N ylcarbamoyl)-4-phenyl-piperidine- 1-carboxylic acid benzyl ester 1 oSo, 93 Example Structure Name M+H 204/° 4-(4-Methanesulfonyl-508 benzylcarbamoyl) 0 0 piperidine-I-carboxylic acid benzyl ester I \ 205 4- (4-Fluoro-benzylcarbamoyl)-4- 448 phenyl-piperidine-l-carboxylic 0) acid benzyl ester N N 206 4- [2- (3-Chloro-phenyl)- 478 n o/ci ethylcarbamoyl]-4-phenyl- piperidine-1-carboxylic acid benzyl ester ester ANH oSon3 207 4-Phenyl-4- [2- (3-trifluoromethyl- 512 F phenyl)-ethylcarbamoyl]- piperidine-I-carboxylic acid benzyl 1 ester estes N S\ 208 4- [(Naphthalen-1-ylmethyl)-480 /o, < carbamoyl]-4-phenyl-piperidine-1- N carboxylic acid benzyl ester H N o°'p I \ 209 o 4-Phenyl-4-(4-trifluoromethyl-498 N benzylcarbamoyl)-piperidine-l- S F F carboxylic acid benzyl ester N oSoX W Example Structure Name M+H 210 0 CH3 4- [ (3-Methyl-benzo [b] thiophen-2- 500 \/o \ ylmethyl)-carbamoyll-4-phenyl- H S piperidine-1-carboxylic acid benzyl ester N \ 211 4- (1-Benzyl-piperidin-4- 513 /N} v ylcarbamoyl)-4-phenyl-piperidine- N) 1-carboxylic acid benzyl ester H N N 212 n 4- [2-(1-Methyl-pyrrolidin-2-yl)-451 0 ethylcarbamoyl]-4-phenyl- N cH3 piperidine-I-carboxylic acid benzyl ester ester N 213 4-(Cyclopropylmethyl-carbamoyl)-394 N 4-phenyl-piperidine-l-carboxylic C acid benzyl ester N 0lio, 214 4-Phenyl-4- (2-pyridin-2-yl- 445 ethylcarbamoyl)-piperidine-l- H carboxylic acid benzyl ester H 1 \ 215 0 4- (Indan-1-ylcarbamoyl)-4-phenyl- 456 piperidine-l-carboxylic acid benzyl H ester N O''O, \ Example Structure Name M+H 216 (-o 4- (2-Morpholin-4-yl- 453 N ethylcarbamoyl)-4-phenyl- N piperidine-I-carboxylic acid benzyl "ester N oo-Y k 217/o/=\ 0 1- [3- (2-Chloro-phenyl)-propionyll- 480 \ 1N \/F 4-phenyl-piperidine-4-carboxylic "acid 4-fluoro-benzylamide N cl/ 218 1- [3- (2-Chloro-phenyl)-propionyl]- 490 0 4-phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-anide ci OY CI/II/ 219 4-Phenyl-l- [3- (4-trifluoromethyl- 514 -N/-F phenyl)-propionyl]-piperidine-4- "carboxylic acid 4-fluor- , N benzylamide w F F 220/t m 4-Phenyl-1-(3-phenyl-propynoyl)-458 N piperidine-4-carboxylic acid 4- N "fluoro-benzylamide N N '3 Example Structure Name M+H 221 4-Phenyl-l- [3- (4-trifluoromethyl- 524 phenyl)-propionyl]-piperidine-4- carboxylic acid (3-phenyl-propyl)- amide N F F F 222 1- [3- (3, 4-Difluoro-phenyl)- 492 propionyl]-4-phenyl-piperidine-4- carboxylic acid (3-phenyl-propyl)- amide N \ F O F 223 4-Phenyl-l- (3-phenyl-propynoyl)- 452 piperidine-4-carboxylic acid (3- phenyl-propyl)-amide N O' 224 \ 1-(4-Methoxy-benzenesulfonyl)-4-494 phenyl-piperidine-4-carboxylic acid (3-phenyl-propyl)-amide nez I \ lu 0 UH3 225 1- [3- (4-Fluoro-phenyl)-propionyl]- 522 4-phenyl-piperidine-4-carboxylic 0 acid (biphenyl-2-ylmethyl)-amide N o /F Example Structure Name M+H 226 0 1- [3- (4-Fluoro-phenyl)-propionyll- 514 F 4-phenyl-piperidine-4-carboxylic "acid 4-trifluoromethyl-benzylamide F F N I/F 227 0 1- [3- (4-Fluoro-phenyl)-propionyl]- 464 N 4-phenyl-piperidine-4-carboxylic acid 4-fluoro-benzylamide N O /F 228 0 1- [3- (4-Fluoro-phenyl)-propionyll- 480 N 4-phenyl-piperidine-4-carboxylic acid 4-chloro-benzylamide N O Y, 229 F 1- [3- (4-Fluoro-phenyl)-propionyl]- 514 4-phenyl-piperidine-4-carboxylic \ F p Y pp Y N acid 3-trifluoromethyl-benzylamide H N N O Y 230 F 1- [3- (4-Fluoro-phenyl)-propionyl]- 582 n Ox F 4-phenyl-piperidine-4-carboxylic N acid 3, 5-bis-trifluoromethyl- H benzylamide F N F <\F 231 0 s 1- [3- (4-Fluoro-phenyl)-propionyll- 452 4-phenyl-piperidine-4-carboxylic acid (thiophen-2-ylmethyl)-amide N u F Example Structure Name M+H. 232 0 1- [3- (4-Fluoro-phenyl)-propionyll- 446 4-phenyl-piperidine-4-carboxylic "acid benzylamide N 0---laF F 233 0 CH3 1- [3- (4-Fluoro-phenyl)-propionyl]- 460 N 4-phenyl-piperidine-4-carboxylic "acid 3-methyl-benzylamide N if 234 0 1- [3- (4-Fluoro-phenyl)-propionyll- 460 \/nez 4-phenyl-piperidine-4-carboxylic acid 4-methyl-benzylamide N O ; 235 cl 1- [3- (4-Fluoro-phenyl)-propionyll- 480 X LN/t 4-phenyl-piperidine-4-carboxylic acid 2-chloro-benzylamide N /F 236--° 1- [3- (4-Fluoro-phenyl)-propionyl]- 472 N 4-phenyl-piperidine-4-carboxylic < acid indan-l-ylamide N O Y 237 0 1- [3- (4-Fluoro-phenyl)-propionylj- 486 4-phenyl-piperidine-4-carboxylic (/acid (1, 2, 3, 4-tetrahydro- naphthalen-1-yl)-amide 01 O Y F Example Structure Name M+H 238 cl 1- [3- (4-Fluoro-phenyl)-propionyll- 494 4-phenyl-piperidine-4-carboxylic N acid [2- (4-chloro-phenyl)-ethyl]- H amide NEZ oY 239 1- [3- (4-Fluoro-phenyl)-propionyl]- 494 n o ~ Cl 4-phenyl-piperidine-4-carboxylic N acid [2- (3-chloro-phenyl)-ethyl]- amide N O 240 F 1- [3- (4-Fluoro-phenyl)-propionyl]- 528 0 4-phenyl-piperidine-4-carboxylic N F F acid [2- (3-trifluoromethyl-phenyl)- H ethyl]-aniide ou O Y 241 C H,, 1- [3- (4-Fluoro-phenyl)-propionylj- 488 4-phenyl-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- "amide 1 cYY F 242, s 1- [3- (4-Fluoro-phenyl)-propionyl]- 466 4-phenyl-piperidine-4-carboxylic A H acid (2-thiophen-2-yl-ethyl)-amide N Oi U F Example Structure Name M+H 243 H 1- [3- (4-Fluoro-phenyl)-propionyl]- 499 0 4-phenyl-piperidine-4-carboxylic \ acid [2- (lH-indol-3-yl)-ethyl]- H amide NEZ 0--loaf 244 1- [3- (4-Fluoro-phenyl)-propionyl]- 488 4-phenyl-piperidine-4-carboxylic vgtN~ acid (4-phenyl-butyl)-amide H N OY\ F 245 1- [3-(4-Fluoro-phenyl)-propionyl]-478 /o F 4-phenyl-piperidine-4-carboxylic N acid [2- (3-fluoro-phenyl)-ethyll- amide N O Y, 246 1- [3- (4-Fluoro-phenyl)-propionyl]- 478 n °\\/Y 4-phenyl-piperidine-4-carboxylic N F acid [2- (2-fluoro-phenyl)-ethyl]- amide N O Y \ F 247 r o 1- [3- (4-Fluoro-phenyl)-propionyl]- 476 \ vN~ W 4-phenyl-piperidine-4-carboxylic acid (2-phenoxy-ethyl)-amide oX N F 248 0 1- [3- (4-Fluoro-phenyl)-propionyl]- 452 4-phenyl-piperidine-4-carboxylic acid cyclohexylmethyl-amide N oW] Example Structure Name M+H F 249 Ft 3-(4-Fluoro-phenyl)-1- {4-[2-(4-518 fluoro-phenyl)-piperidine-l- carbonyl]-4-phenyl-piperidin-l- yl}-propan-1-one N N F 250 cl 1- [3- (4-Fluoro-phenyl)-propionyll- 507 4-phenyl-piperidine-4-carboxylic ruz acid (5-chloro-benzooxazol-2-yl)- 0 < -o amide zon N H O F M 251 1- [3- (4-Fluoro-phenyl)-propionyl]- 512 4-phenyl-piperidine-4-carboxylic acid (2-methyl-5-phenyl-2H- n ok XNN pyrazol-3-yl)-amide A H CH3 nu H CH, N 252 1- [3- (4-Fluoro-phenyl)-propionyl]- 515 4-phenyl-piperidine-4-carboxylic . { acid (4-phenyl-thiazol-2-yl)-amide ors 0 -xs ? N H N "N 253 0 N 1- [3- (4-Fluoro-phenyl)-propionyl]- 486 N 4-phenyl-piperidine-4-carboxylic H acid (lH-benzoimidazol-2- N ylmethyl)-amide oM F Example Structure Name 254 0 1- [3- (4-Fluoro-phenyl)-propionyll- 461 4-phenyl-piperidine-4-carboxylic X \CH3 acid methyl-pyridin-2-ylmethyl- amide N O Y F 255 o/==N l- [3- (4-Fluoro-phenyl)-propionyl]- 461 \/N 4-phenyl-piperidine-4-carboxylic C X CH3 aC1d BOthY1 PYndin 3 Y1methY1 oH amide N I F 256 1- [3- (4-Fluoro-phenyl)-propionyll- 490 o ° ~ 4-phenyl-piperidine-4-carboxylic \ N, o acid [2- (2-methoxy-phenyl)-ethyl]- H CH3 amide N °i U F 257 Br 1- [3- (4-Fluoro-phenyl)-propionyl]- 538 4-phenyl-piperidine-4-carboxylic v SN/acid [2-(4-bromo-phenyl)-ethyl]- H amide N O Y I F 258 H3 1- [3- (4-Fluoro-phenyl)-propionyll- 474 4-phenyl-piperidine-4-carboxylic xi acid (2-p-tolyl-ethyl)-amide zon H zon N Example Structure Name M+H 259 °, c"3 1- [3- (4-Fluoro-phenyl)-propionyl]- 520 4-phenyl-piperidine-4-carboxylic 1°\ acid [2- (2, 5-dimethoxy-phenyl)- ethyl]-amide N o0 "cl3 N O I F 260 <, o) 1- [3-(4-Fluoro-phenyl)-propionyl]-504 0 4-phenyl-piperidine-4-carboxylic \/N acid (2-benzo [1, 3] dioxol-5-yl- "ethyl)-amide N O F 261 1- [3- (4-Fluoro-phenyl)-propionyl]- 528 4-phenyl-piperidine-4-carboxylic acid [2- (3, 4-dichloro-phenyl)- <) H ethyl]-amide N N 262 c"3 1- [3- (4-Fluoro-phenyl)-propionyl]- 488 4-phenyl-piperidine-4-carboxylic N N~ ACH3 acid [2- (2, 4-dimethyl-phenyl)- H ethyl]-amide N' N F 263 CH3 1- [3- (4-Fluoro-phenyl)-propionyll- 488 4-phenyl-piperidine-4-carboxylic /O C"a \ N acid [2- (3, 4-dimethyl-phenyl)- H ethyl]-amide N O Y \ F Example Structure Name M+H 264 1- [3- (4-Fluoro-phenyl)-propionyl]- 474 C) oN/4-phenyl-piperidine-4-carboxylic N CH3 acid (2-o-tolyl-ethyl)-amide H cl N I/F 265 1- [3- (4-Fluoro-phenyl)-propionylj- 474 0 CH, 4-phenyl-piperidine-4-carboxylic N acid (2-m-tolyl-ethyl)-amide H N 0--aF F 266 0 cH3 1- [3- (4-Fluoro-phenyl)-propionyl]- 516 N/4-phenyl-piperidine-4-carboxylic H acid (3-methyl-benzo [b] thiophen- 2-ylmethyl)-amide o Y \ N O-F 267 n i 4-Phenyl-4-[(pyridin-2-ylmethyl)-431 WHv q carbamoyl]-plperidine-l- /carboxylic acid benzyl ester N oo X 268 0 4-Phenyl-4- (pyridin-2- 416 N N ylcarbamoyl)-piperidine-l- "carboxylic acid benzyl ester N oo \ Example Structure Name M+H 0 269 n 0 1 4- (2-Methoxy-pyridin-3- 447 w N w N ylcarbamoyl)-4-phenyl-piperidine- 1-carboxylic acid benzyl ester N 1 0 C EXAMPLE 270

Synthesis

Compound 1: Compound 1 were prepared using methodology described in Example 85.

Compound 2 : A solution of compound 1 (1.26 g; 4.03 mmol) in anhydrous acetonitrile (25 mL) was treated with diphenyl N-cyanocarbonimidate (l. Og ; 4.2 mmol) and heated at 85°C for 1.5 h. The acetonitrile was removed by evaporation and the crude residue was purified by column chromatography on silica gel using a 7: 3 hexane: ethyl acetate to 1: 1 hexane: ethyl acetate gradient as the eluent to give 0.51 g of compound 2 as a white solid. LCMS nilz = 338 (M+H) + Title Compound: A solution of compound 2 (0.081 g; 0.18 mol) in isopropanol (5 mL) was treated with benzyl amine (0.04 mL; 0.37 mmol) and heated at 90°C for 15 h. The isopropanol was removed by evaporation and the crude residue was purified by recrystallization from ethyl acetate/hexane to give 0.061 g of the title compound as white crystals. LCMS m/z = 471 (M+H) + EXAMPLES 271 TO 274 Examples 271 to 274 were prepared using methodology described in Example 270. Example Structure Name M+H 0 271 XHSF 408 - I N NAN ACH3 N N III H 272 0 423 N 1 CHs N F Example Structure Name M+H 273 X H nF _ 408 N N N N chia N 274 /o _ 380 N ,/F N-NHs JE N''NHz N NH2 EXAMPLE 275

4-Phenyl-1-sulfamoyl-piperidine-4-carboxylic acid benzylamide Synthesis 0 O OSp/I p \ H2N \NH2 \ N \ H H I N 1, 4-Dioxane, A N Ni H I O=S=O 1 NH2 Compound 1: Compound 1 was prepared as described in Example 85.

Title Compound: 4-Phenyl-l-sulfamoyl-piperidine-4-carboxylic acid benzylamide was prepared using methodology described in Example 15. 1H NMR

(CDC13, rt): 8 ppm) 2.15-2. 24 (2 H, m), 2.50-2. 55 (2 H, m), 3.21-3. 27 (2 H, m), 3.42- 3.49 (2 H, m), 4.28 (2 H, s), 4.36 (2 H, d, J = 5. 9 Hz), 5.47 (1 H, bs), 7.02 (2 H, d, J = 7.5 Hz), 7.23 (2 H, d, J = 1.9 Hz), 7.30-7. 41 (6 H, m). LCMS Rt 1.45 min, [M+1] 374.0.

EXAMPLE 276 1-Dimethylsulfamoyl-4-phenyl-piperidine-4-carboxylic acid benzylamide Scheme o I o N ) OHs) 2NS02CI N H I/H I/ I ION 2 2) AP-Trisamine O=S=O 1 N Compound 1: Compound 1 was prepared as described in Example 85.

Title Compound: 1-Dimethylsulfamoyl-4-phenyl-piperidine-4-carboxylic acid benzylamide was prepared using methodology described in Example 16. 1H NMR (CDC13, rt): 8 ppm) 2.13-2. 22 (2 H, m), 2.42-2. 49 (2 H, m), 2.80 (6 H, s), 3.31- 3.45 (4 H, m), 4.34 (2 H, d, J = 5. 7 Hz), 4.28 (2 H, s), 5.47 (1 H, bs), 7.02 (2 H, t, J = 5.0, Hz), 7.21-7. 25 (2 H, m), 7.27-7. 41 (6 H, m). LCMS Rt 1.59 min, [M+1] 402.0.

EXAMPLE 277

1- (2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidine-4-carboxylic acid benzylamide Scheme

Compound 1: Compound 1 was prepared as described in Example 85.

Compound 2: Compound 2 was prepared as described in Example 17.

Title Compound: 1- (2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidine-4- carboxylic acid benzylamide was prepared using methodology described in Example 17. 1H NMR (CDC13, rt): 5 ppm) 2.15-2. 24 (2 H, m), 2.44-2. 51 (2 H, m), 3.11-3. 25 (2 H, m), 3.30-3. 43 (6 H, m), 3.48 (2 H, t, J = 5. 2 Hz), 4.34 (2 H, d, J = 5. 7 Hz), 4.51 (1 H, bs), 5.46 (1 H, s), 7.01-7. 25 (4 H, m), 7.29-7. 41 (7 H, m). LCMS Rt 1.47 min, [M+1] 432.3.

EXAMPLES 278 TO 285 Example 278 to 285 were prepared using methodology described in Example 277. Example Structure Name M+H _ v I 278 n o n 1-(4-Fluoro-benzylsulfamoyl)-4-phenyl-470 9/N/ANJ piperidine-4-carboxylic acid pyridin-2- H ylamide N I or HAN F F 279 n o n 1-(2-Methoxy-ethylsulfamoyl)-4-phenyl-420 N'CN piperidine-4-carboxylic acid pyridin-2- H ylaniide N I HN HAN 0H I CH, 280 i o i 1- (4-Fluoro-benzylsulfamoyl)-4-phenyl- 500 N N piperidine-4-carboxylic acid (2-methoxy- 1 H oHO pyridin-3-yl)-amide jan "N 0=S=0 HO F 281 IN 1- (2-Methoxy-ethylsulfamoyl)-4-phenyl- 450 piperidine-4-carboxylic acid (2-methoxy- pyridin-3-yl)-amide N I 0= HIT CHO C. H3 Example Structure Name M+H 282 1 0 N- [I- (4-Fluoro-benzylsulfamoyl)-4- 482 N phenyl-piperidin-4-ylmethyl]-2-methoxy- H benzamide o=s=o HO i F 283 n ° N-(l-Benzylsulfamoyl-4-phenyl-464 N piperidin-4-ylmethyl)-2-methoxy- benzamide N i o=s=o HAN. han 284 0 2-Methoxy-N- (4-phenyl-l- 416 propylsulfamoyl-piperidin-4-ylmethyl)- benzamide N i O=S=o HO 285 n1 o N-(l-Dimethylsulfamoyl-4-phenyl-432 piperidin-4-ylmethyl)-2-methoxy- N benzamide o=s=o UN. lao I EXAMPLE 286

4-phenyl-1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid (biphenyl-3-ylmethyl)-amide Synthesis

Compound 1: Compound 1 is commercially available.

Compound 2: A suspension of compound 1 (3.53 g; 9.35 mmol) in 50 mL of tetrahydrofuran was treated with triethylamine (2.9 mL ; 20.8 mmol) and the reaction mixture was cooled to 0°C. Hydrocinnamoyl chloride (1.92 g; 11.4 mmol) was added as a solution in 5 mL of tetrahydrofuran. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 h. The tetrahydrofuran was removed by evaporation and the residue was treated with ethyl acetate (approximately 150 mL) and 10% aqueous hydrochloric acid (approximately 100 mL). The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. The crude product was purified by recrystallization from ethanol to give 1.02 g of compound 2 as a white solid. LCMS m/z = 338 (M+H) + Compound 3: A suspension of compound 2 (0.23 g; 0.67 mmol) in 12 mL of dichloromethane was treated with triethylamine (0.14 mL ; 1.0 mmol) followed by fluoro-N, N, N',-tetramethylformamidinium hexafluorophosphate (0.22 g; 0.83 mmol) at room temperature. After stirring for 1 h, the dichloromethane was removed by evaporation to give 0.23 g of compound 3 that was used in the next step without further purification. LCMS 77z/z = 340 (M+H) + Title Compound: A solution of compound 3 (0.13 g; 0.39 mmol) in 15 mL of dichloromethane was treated with triethylamine (0.071 mL ; 0.51 mmol) followed by

2-phenylbenzyl amine (0. 074 mL ; 0.043 mmol) at room temperature. After stirring for 8 h, an additional 50 mL of dichloromethane an 40 mL of 10% aqueous hydrochloric acid was added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 1: 1 hexane: ethyl acetate as the eluent gave 0.16 g of 4-phenyl-1- (3-phenyl-propionyl)-piperidine-4-carboxylic acid (biphenyl-3- ylmethyl) -amide as a white solid. m/z = 504 (M+H) +.

EXAMPLE 287

4-Phenyl-1- (3-phenyl-propionyl)-piperidine-4-carboxylic acid methyl-phenethyl-amide Synthesis

Compound 1: Compound 1 was prepared as described in Example 286.

Title Compound: Compound 1 (0.015 g; 0.05 mmol) was dissolved in 1 mL acetonitrile. Polystyrene-diisopropylethylamine (PS-DIEA) resin (0. lg) was added and the resulting suspension was treated with N-methylphenethylamine 0.02 g; 0.1 mmol) and shaken at room temperature. After 24 h, polystyrene-tosyl chloride, high

loading (PS-TsCl) resin (0.2 g) was added and the reaction mixture was allowed to shake an additional 24 h. The reaction mixture was filtered and concentrated to give 0.010 g of 4-Phenyl-1- (3-phenyl-propionyl)-piperidine-4-carboxylic acid methyl- phenethyl-amide as a colorless oil. LCMS n/z = 456 (M+H) + EXAMPLES 288 TO 322 Examples 288 to 322 were prepared using methodology described in Example 287. Example Structure Name M+H 288 4-Phenyl-l- (3-Phenyl-propionyl)- 504 piperidine-4-carboxylic acid XN< (biphenyl-3-ylmethyl)-amide H N O' i 289 0 CH3 4-Phenyl-l- (3-phenyl-propionyl)- 442 -N piperidine-4-carboxylic acid 3- methyl-benzylamide N i 290 0 4-Phenyl-l- (3-phenyl-propionyl)- 462 piperidine-4-carboxylic acid 4- H Iz C, chloro-benzylamide N i 291 0 CH3 4-Phenyl-l- (3-phenyl-propionyl)- 442 piperidine-4-carboxylic acid (1- H phenyl-ethyl)-amide N OY Example Structure Name M+H 292 4-Phenyl-l- (3-phenyl-propionyl)- 456 piperidine-4-carboxylic acid (2- \ N CH phenyl-propyl)-amide H jan 293 o P"'3 4-Phenyl-l- (3-phenyl-propionyl)- 394 piperidine-4-carboxylic acid sec- H CHs butylamide N Ov 294 4-Phenyl-l- (3-phenyl-propionyl)- 454 0 piperidine-4-carboxylic acid indan- N 2-ylamide H f) N OY 295 CH3 4-Phenyl-1-(3-phenyl-propionyl)-488 ; piperidine-4-carboxylic acid 2, 6- X NX~) dimethoxy-benzylamide N N / 296 4-Phenyl-l- (3-phenyl-propionyl)- 496 0 FF piperidine-4-carboxylic acid 3- N trifluoromethyl-benzylamide H I ""T 297 0 4-Phenyl-l- (3-phenyl-propionyl)- 406 N piperidine-4-carboxylic acid H cyclopentylamide N Example Structure Name M+H 298 0 4-Phenyl-l- (3-phenyl-propionyl)- 442 N\ piperidine-4-carboxylic acid Ç benzyl-methyl-amide N O' i 299 4-Phenyl-l- (3-phenyl-propionyl)- 470 piperidine-4-carboxylic acid (2- n °) /hydroxy-indan-l-yl)-amide N'oh N N 50H UNI 300 4-Phenyl-l- (3-phenyl-propionyl)- 522 piperidine-4-carboxylic acid O N benzyl- (1-methyl-lH-imidazol-2- ylmethyl)-amide N N CL3 0 1 301 0 3-Phenyl-l- [4-phenyl-4- (4-pyridin- 484 t W N N 2-yl-piperazine-1-carbonyl)- Ç N piperidin-1-yl]-propan-1-one N O' Y, Ui 302 0 3-Phenyl-l- [4-phenyl-4- (4- 485 <N N pyrimidin-2-yl-piperazine-1- X xNXN) carbonyl)-piperidin-l-yl]-propan-l- N : one O' N 303 1-14- [4- (4-Chloro-phenyl)-517 piperazine-l-carbonyl]-4-phenyl- C\ 1 N \/W piperidin-1-yl}-3-phenyl-propan-1- one """0 i Example Structure Name M+H 304 H 4-Phenyl-l- (3-phenyl-propionyl)- 481 N piperidine-4-carboxylic acid [2- (lH-indol-3-yl)-ethyl]-amide N H N i 305 0 1- [4- (3, 4-Dihydro-lH- 454 . <NC isoquinoline-2-carbonyl)-4-phenyl- piperidin-1-yl]-3-phenyl-propan-l- one M zizi 306 H 4-Phenyl-l- (3-phenyl-propionyl)- 480 piperidine-4-carboxylic acid (5- <, SN phenyl-lH-pyrazol-3-yl)-amide H f oY Ui 307 0 1-f 4- [4- (2-Chloro-phenyl)- 517 N/__)-1-carbonyl]-4-phenyl- piperidin-1-yll-3-phenyl-propan-l- one N i 308/O F 4-Phenyl-1-(3-phenyl-propionyl)-464 piperidine-4-carboxylic acid 3, 4- H difluoro-benzylamide N O, /CN-b 4-Phenyl-l- (3-phenyl-propionyl)- 497 N piperidine-4-carboxylic acid (1- H benzyl-pyrrolidin-3-yl)-amide N Ii Example Structure Name M+H 310 0 4-Phenyl-l- (3-phenyl-propionyl)- 506 '---a CH3 piperidine-4-carboxylic acid 4- methanesulfonyl-benzylamide oR/4 N i 311 0 4-Phenyl-l- (3-phenyl-propionyl)- 446 N'--F piperidine-4-carboxylic acid 4- H fluoro-benzylamide N i 312 4-Phenyl-l- (3-phenyl-propionyl)- 476 piperidine-4-carboxylic acid [2- (3- N chloro-phenyl)-ethyl]-amide JAN "N 01c 313 < F 4-Phenyl-1-(3-phenyl-propionyl)-510 n O F piperidine-4-carboxylic acid [2- (3- Cxf F trifluoromethyl-phenyl)-ethyl]- t ! amide 09 OY i 314 4-Phenyl-l- (3-phenyl-propionyl)- 478 0 piperidine-4-carboxylic acid N (naphthalen-1-ylmethyl)-amide H I 0-Y i 315 0 4-Phenyl-l- (3-phenyl-propionyl)- 496 F piperidine-4-carboxylic acid 4- tN) H F trifluoromethyl-benzylamide Oui ----a Example Structure Name M+H 316 + CH3 4-Phenyl-1- (3-phenyl-propionyl)- 498 piperidine-4-carboxylic acid (3- methyl-benzo [b] thiophen-2- methyl T w Ii 317 4-Phenyl-l- (3-phenyl-propionyl)- 511 piperidine-4-carboxylic acid (1- N benzyl-piperidin-4-yl)-amide N N xi 318 4-Phenyl-l- (3-phenyl-propionyl)- 449 N piperidine-4-carboxylic acid [2- (1- <0N CH3 methyl-pyrrolidin-2-yl)-ethyl]- amide N o"Y 319 0 4-Phenyl-l- (3-phenyl-propionyl)- 392 piperidine-4-carboxylic acid H cyclopropylmethyl-amide N i 320 4-Phenyl-l- (3-phenyl-propionyl)- 443 g) O/N piperidine-4-carboxylic acid (2- N pyridin-2-yl-ethyl)-amide H N < H Zizi o-Yi 321 0 4-Phenyl-l- (3-phenyl-propionyl)- 454 \ N piperidine-4-carboxylic acid indan- 1-ylamide N oY i Example Structure Name 53 322 0 4-Phenyl-l- (3-phenyl-propionyl)- 451 f) O NJ piperidine-4-carboxylic acid (2- N morpholin-4-yl-ethyl)-amide N %. H Ut I EXAMPLE 323

4-(Benzylcarbamoyl-methyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester Synthesis SOH 1. W X'XN2 0 0 0 OH 1, , OH 1. S02CI C. N 2. CH2N N N IF, H TsOH NaOH, CH2C12 oXoX Et20 O ; OX soh 0 2. HCI 3 1 2 3 N \OH -\NJ 1. hv, MeOH 0 BnNH2 0 - N N 2. LiOH, dioxane OO NEP OO 01'o-, NEt3 o o'--10-- THF 4

Compound 1: Compound 1 is commercially available.

Compound 2: Benzyl chloroformate (4.75 mL, 33.1 mmol) was added dropwise to a solution of 4-phenyl-4-piperidinecarboxylic acid p- methylbenzenesulfonate (10.0 g, 26.5 mmol) in 1M sodium hydroxide (200 mL)/ dichloromethane (100 mL). After 2 hours the reaction mixture was made acidic with 1M hydrochloric acid (pH = 3), the organic layer was separated and the aqueous layer extracted with ethyl acetate (3 x 100 mL). The organic layers were collected, concentrated and crude product washed with water (3 x 50 mL) to give 8.52 g of 4- phenyl-piperidine-1, 4-dicarboxylic acid monobenzyl ester. LRMS m/z 340.2 (M+H) +.

Compound 3: Thionyl chloride (4.29 mL, 58.9 mmol) was added to 4- Phenyl-piperidine-1,4-dicarboxylic acid monobenzyl ester (2.00 g, 5.89 mmol) and heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, taken up in ethyl ether (25 mL), cooled to 0 °C and diazomethane in ethyl ether was (30.0 mmole, 100 mL) added. After completion of the reaction, as monitored by thin layer chromatography, the excess diazomethane was quenched with acetic acid (5 mL). The reaction mixture was concentrated under reduced pressure and crude product purified by column chromatography to give 1.27 g of 4- (2-diazo- acetyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester.

Compound 4: 4-(2-Diazo-acetyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester (1.50 g, 4.12 mmol) in methanol (40 mL) was irradiated under UV (a365 nM) for 36 hours. The reaction mixture was concentrated under reduced pressure, crude product taken up in 3M lithium hydroxide (20 mL)/dioxane (20 mL) and heated to 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove dioxane, made acidic with 6M hydrochloric acid, and extracted with ethyl acetate (6 x 50 mL). Organic layers were collected, concentrated and crude product purified by column chromatography to give 1.16 g of 4-carboxymethyl-4- phenyl-piperidine-l-carboxylic acid benzyl ester. 1H NMR (CD3C13, 300 MHz) 8 7.32 (m, 10H), 5.10 (s, 2H), 3.76 (d, 2H, J = 13. 4 Hz), 3.20 (t, 2H, J = 10. 7 Hz), 2.56 (s, 2H), 2. 31 (d, 2H, J = 13.6 Hz), 1. 91 (t, 2H, J = 13.0 Hz).

Title Compound : Benzotriazol-l-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.120 g, 0.271 mmol) was added to a solution of benzyl amine

(0.030 mL, 0.271 mmol), 4-carboxymethyl-4-phenyl-piperidine-1-carboxylic acid benzyl ester (0.100 g, 0.247 mmol), triethylamine (0.103 mL, 0.741 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2 x 10 mL). Organic layer collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.099 g of 4- (benzylcarbamoyl- methyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester. LRMS m/z 443.2 (M+H) +.

EXAMPLE 324

N- [2- (2-Fluoro-phenyl)-ethyl]-2- {l- [3- (4-fluoro-phenyl)-propionyl]-<BR> 4-phenyl-piperidin-4-yl}-acetamide Synthesis

Compound 1: Compound 1 were prepared using methodology described in Example 323.

Compound 2: Ammonium formate (1.00 g) was added to a solution of 4- { [2- (2-fluoro-phenyl)-ethylcarbamoyl]-methyl}-4-phenyl-piperidin e-1-carboxylic acid benzyl ester (0.520 g, 1.10 mmol) in methanol (50 mL) containing 10% palladium/carbon (0.500 g) and stirred for 4 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude product was taken up in 1M sodium hydroxide (100 mL) and extracted with ethyl acetate (3 x 50 mL).

The organic layers were collected and concentrated under reduced pressure to give 0.328 g (87%) of N- [2- (2-fluoro-phenyl)-ethyl]-2- (4-phenyl-piperidin-4-yl)- acetamide. LRMS m/z 341.1 (M+H) +.

Title Compound: Benzotriazol-l-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.311 g, 0.704 mmol) was added to a solution of N- [2- (2- fluoro-phenyl)-ethyl]-2- (4-phenyl-piperidin-4-yl)-acetamide (0.200 g, 0.587 mmol), 3- (4-Fluoro-phenyl) -propionic acid (0.118 g, 0.704 mmol) and triethylamine (0.245 mL, 1.76 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2 x 10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography on silica gel to give 0.098 g (34 %) ofN- [2- (2-fluoro-phenyl)-ethyl]-2- {l- [3- (4-fluoro-phenyl)- propionyl]-4-phenyl-piperidin-4-yl}-acetamide. LRMS mXz 491. 1 (M+H) +.

EXAMPLES 325 TO 380 Examples 325 to 380 were synthesized using methodology described in Example 324. Example Structure Name M+H 325 X H S 4-Phenyl-4-{ [(thiophen-2-450 vNX, ylmethyl)-carbamoyl]-methyl}- piperidine-1-carboxylic acid benzyl ester N 326 \ H 4-Phenyl-4- [ (1-phenyl- 458 +lynx ethylcarbamoyl)-methyl]- O CH piperidine-1-carboxylic acid benzyl 0 CH, ester w 327 H 4- [ (2-Methoxy-benzylcarbamoyl)- 474 N methyl]-4-phenyl-piperidine-1- II carboxylic acid benzyl ester oSoX3 N" w 328 4- [ (3-Methoxy-benzylcarbamoyl)- 474 N w o, cH3 methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester I NI k 329 H O'CH3 4- [ (4-Methoxy-benzylcarbamoyl)- 474 N < methyl]-4-phenyl-piperidine-1- ) o carboxylic acid benzyl ester I oo-Y 'k 330 H 4- [ (2, 3-Dimethoxy- 504 , N wl N-CH3 benzylcarbamoyl)-methyl]-4- phenyl-piperidine-1-carboxylic acid benzyl ester oxo Example Structure Name M+H 331 0CH3 4- [ (2, 4-Dimethoxy- 504 \>N Jg benzylcarbamoyl)-methyl]-4- 0 O-CH3 phenyl-piperidine-l-carboxylic acid benzyl ester oo 332 \ H 4- [ (3-Methyl-benzylcarbamoyl)- 458 N CH methyl]-4-phenyl-piperidine-1- 0 3 carboxylic acid benzyl ester N N I w 333 H CH3 4- [ (4-Methyl-benzylcarbamoyl)- 458 N,w methyl]-4-phenyl-piperidine-1- 0 carboxylic acid benzyl ester I N p^p I w 334 8, gF 4-[(4-Fluoro-benzylcarbamoyl)-462 H methyl]-4-phenyl-piperidine-l- 0 carboxylic acid benzyl ester ! J o I ooY 335 \ H 4- [ (2-Chloro-benzylcarbamoyl)- 478 N methyl]-4-phenyl-piperidine-1- t O Cl carboxylic acid benzyl ester ! J 0 C ! I N 336 n H wCI 4-[(4-Chloro-benzylcarbamoyl)-478 +nNX methyl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester N Y 0A04 Example Structure Name M+H 337 F 4-Phenyl-4- [ (3-trifluoromethyl- 512 benzylcarbamoyl)-methyl]- H piperidine-1-carboxylic acid benzyl N ester 0 N w 338 F F 4-Phenyl-4- [ (4-trifluoromethyl- 512 n H XF benzylcarbamoyl)-methyl]- N piperidine-I-carboxylic acid benzyl 0 ester I N 339 < H 4-(Phenethylcarbamoyl-methyl)-4-458 N phenyl-piperidine-1-carboxylic acid benzyl ester ! J o N 340/\ H F 4- { [2- (2-Fluoro-phenyl)- 476 N ethylcarbamoyl]-methyl}-4-phenyl- 0 piperidine-I-carboxylic acid benzyl N ester 0A09 w 341 H 4-1 [2- (3-Fluoro-phenyl)- 476 N XF ethylcarbamoyl]-methyl}-4-phenyl- piperidine-1-carboxylic acid benzyl N ester I w 342 < H 4-{ [2-(4-Fluoro-phenyl)-476 \DSANN S, ethylcarbamoyl]-methyl}-4-phenyl- piperidine-1-carboxylic acid benzyl ester O O i Example Structure Name M+H 343 n H F 4-Phenyl-4-{[2-(3-trifluoromethyl-526 N F phenyl)-ethylcarbamoyll-methyll- tNj ° W piperidine-1-carboxy1icacidbenzy N ester 0X0n 344 n H 4- { [2-(4-Ethyl-phenyl)-486 \>N n ethylcarbamoyl]-methyl}-4-phenyl- N 0 CH3 piperidine-1-carboxylic acid benzyl N ester oxo 345 H H o, CH3 4-{ [2-(2, 5-Dimethoxy-phenyl)-518 N g4 ethylcarbamoyl]-methyl}-4-phenyl- tNX ° 9 piperidine-1-carboxylic acid benzyl ester w CHs O O i 346 4-Phenyl-4-{ [(pyridin-3-ylmethyl)-445 H N carbamoyl]-methyl}-piperidine-l- NX carboxylic acid benzyl ester 1 , r-oo 0---o W 347 4-Phenyl-4- { [ (pyridin-4-ylmethyl)- 445 H carbamoyll-methyll-piperidine-l- tX otWg carboxylic acid benzyl ester I 0-0 ' 348 n 4-Phenyl-4- [ (2-pyridin-4-yl- 459 ethylcarbamoyl)-methyl]- N piperidine-1-carboxylic acid benzyl ester O'\O k 349/\ 2- {l- [3- (4-Fluoro-phenyl)- 474 -4-phenyl-piperidin-4- 0 cH3 yl}-N- (l-phenyl-ethyl)-acetamide N O F Example Structure Name M+H 350 N- (l-Phenyl-ethyl)-2- [4-phenyl-l- 456 N (3-phenyl-propionyl)-piperidin-4- tX O CH3 yl]-acetamide 0 cl3 N W0 351 H 2-fl- [2- (4-Fluoro-phenyl)-acetyll- 460 N 4-phenyl-piperidin-4-yll-N- (l- O CH3 phenyl-ethyl)-acetamide N 0 / F 352 H 2- [l- (4-Fluoro-benzoyl)-4-phenyl- 446 piperidin-4-yl]-N- (l-phenyl-ethyl)- acetamid 0 cl3 N O F 353 H 2- [I- (2, 3-Difluoro-benzoyl)-4- 464 N phenyl-piperidin-4-yl]-N- (l- O CH phenyl-ethyl)-acetamide 3 N F SO 0 354/\, 'N- (l-Phenyl-ethyl)-2- [4-phenyl-l- 482 e N JU (2, 4, 5-trifluoro-benzoyl)-piperidin- C O CH3 4-yl]-acetamide fro N F ==0 F F Example Structure Name M+H 355 H F N- [2- (2-Fluoro-phenyl)-ethyl]-2- 474 \ N [4-phenyl-1- (3-phenyl-propionyl)- piperidin-4-yl]-acetamide N W0 356 2- {l- [2- (4-Fluoro-phenyl)-acetyl]- 478 \ _,,,, b 4-phenyl-piperidin-4-yll-N- [2- (2- fluoro-phenyl)-ethyl]-acetamide N "N 0 F 357 H F 2- [l- (4-Fluoro-benzoyl)-4-phenyl- 464 \ \ F piperidin-4-yl]-N- [2- (2-fluoro- S O W phenyl)-ethyl]-acetamide N O F 358 H F 2- [I- (2, 3-Difluoro-benzoyl)-4- 482 phenyl-piperidin-4-yl]-N- [2- (2- (> fluoro-phenyl)-ethyl]-acetamide 0 N F <, 359 H F N- [2- (2-Fluoro-phenyl)-ethyl]-2- 500 [4-phenyl-l- (2, 4, 5-trifluoro- benzoyl)-piperidin-4-yl]-acetamide N F O F F Example Structure Name M+H 360 HC 4-[(2-Methoxy-phenylcarbamoyl)-460 N methyll-4-phenyl-piperidine-l- , carboxylic acid benzyl ester m0X0 w 361 4-Phenyl-4-1 [ (pyridin-2-ylmethyl)- 445 HN (N carbamoyl]-methyl}-piperidine-1- carboxylic acid benzyl ester N 0 362 4-Phenyl-4-[(lH-pyrazol-3-419 w I N N ylcarbamoyl)-methyl]-piperidine-1- 0 carboxylic acid benzyl ester Chai 0--T-O X 363 H 4- (Isoxazol-3-ylcarbamoylmethyl)- 420 w NN 4-phenyl-piperidine-1-carboxylic t acid benzyl ester N 00 f3 364 H 4- [ (3-Methyl-isoxazol-5- 435 w X N O ylcarbamoyl)-methyl]-4-phenyl- t 9 O 9 piperidine-l-carboxylic acid benzyl N CH3 ester X i 365 H 4- [ (5-Methyl-isoxazol-3- 435 wX) (N>CH3 ylcarbamoyl)-methyl]-4-phenyl- 0 0 N-o piperidine-l-carboxylic acid benzyl N ester X b Example Structure Name M+H 366 H 4-Phenyl-4- (thiazol-2- 437 N S ylcarbamoylmethyl)-piperidine-l- N carboxylic acid benzyl ester N 0A0 i 367 H 4-Phenyl-4- ( [1, 3, 4] thiadiazol-2-438 Ny S ylcarbamoylmethyl)-piperidine-l- N-N carboxylic acid benzyl ester N N 0--T-O X 368 H H 4-Phenyl-4-[(lH-tetrazol-5-421 vXNNx ylcarbamoyl)-methyl]-piperidine-1- 4 j O N-N carboxylic acid benzyl ester N cor\) 369/H 4-[(2-Ethyl-2H-pyrazol-3-448 N ylcarbamoyl)-methyl]-4-phenyl- 0 N-N piperidine-1-carboxylic acid benzyl N ester CH3 O O i 370 4- [ (2, 5-Dimethyl-2H-pyrazol-3- 448 N ylcarbamoyl)-methyl]-4-phenyl- X CW piperidine-l-carboxylic acid benzyl N Cj-3 N-ester %. x CH3 ester 0--l-0 b Example Structure Name M+H 371 H 4- (Benzothiazol-2- 487 N ylcarbamoylmethyl)-4-phenyl- 0 ° St piperidine-l-carboxylic acid benzyl ester N 0--l-0 1-0 372 4-l : (3-Methyl-isothiazol-5-451 ylcarbamoyl)-methyl]-4-phenyl- ,-CH, piperidine-t-carboxylic acid benzyl N zester N 1-0 373 r\ 4-Phenyl-4- [ (5-phenyl-2H-pyrazol- 496 wNX < \ 3-ylcarbamoyl)-methyl]-piperidine- -carboxylic acid benzyl ester N N w 374/\ 4-Phenyl-4- [ (5-phenyl-oxazol-2- 497 N O ylcarbamoyl)-methyl]-piperidine-l- y carboxylic acid benzyl ester N N i 375 H 4- [ (5-Chloro-benzooxazol-2- 505 N N ylcarbamoyl)-methyl]-4-phenyl- 0 o/\ piperidine-1-carboxylic acid benzyl - b-CI N ester 0--l-0 i Example Structure Name M+H 376 H 4-Phenyl-4- [ (5-trifluoromethyl- 506 H N N [1, 3, 4] thiadiazol-2-ylcarbamoyl)- < XN methyl]-piperidine-1-carboxylic A FFXF acid benzyl ester N SF-F zu b 377/\4- [ (2-Methyl-5-phenyl-2H-pyrazol- 510 N 3-ylcarbamoyl)-methyl]-4-phenyl- t 3 o N-Nm piperidine-l-carboxylic acidbenzyl N CHS ester 3 "0 378/\ 4- [ (5-0xo-l-phenyl-4, 5-dihydro- 512 N IH-pyrazol-3-ylcarbamoyl)- 0 methyll-4-phenyl-piperidine-l- N 0 carboxylic acid benzyl ester 00 '0 379/\ 4-PhenyI-4- [ (4-phenyl-thiazoI-2- 513 N ylcarbainoyl)-methyl]-piperidine-l- ) jo carboxylic acid benzyl ester s N o 380 H O'CH3 N- (2-methoxy-phenyl)-2- [4- 458 N Nd phenyl-1- (3-phenyl-propionyl)- piperidin-4-yl]-acetamide 0 N c EXAMPLE 381

2- [1- (4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-yl]- N- (2-methoxy-phenyl)-acetamide Synthesis CH, CSO2CI NtCH3 H '-X-T'C& U 0 (ins O N N 2. PS-trisamine O=S=O H 1 F

Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS nz/z 325 (M+H) +.

Title compound: 2- [l- (4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-yll- N- (2-methoxy-phenyl)-acetamide was prepared using methodology described in Example 95. LRMS/ 484 (M+H) +.

EXAMPLE 382

N- (2-Methoxy-phenyl)-2- (4-phenyl-l-pyrimidin-2-yl-piperidin-4-yl)-acetamide Synthesis

Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS m/z 325 (M+H) +.

Title Compound : N- (2-Methoxy-phenyl)-2- (4-phenyl-1-pyrimidin-2-yl- piperidin-4-yl) -acetamide was prepared using methodology described in Example 521.

LRMS m/z 403 (M+H) +.

EXAMPLE 383 Synthesis

Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS inlz 325 (M+H) +.

Compound 2: Compound 2 was prepared using methodology described in Example 25. LRMS mlz 470 (M+H) +.

Title Compound: The title compound was prepared using methodology described in Example 25. LRMS filz 421 (M+H) +.

EXAMPLES 384 AND 385 Examples 384 and 385 was prepared using methodology described in Example 383.

Example Structure Name (M+H) 384 X H00) CH3 483 SI ; N3 NN-Y 6 N lu po 385, H pCHs 497 OXY 0 N_b . 0 N "-"0 N-CN EXAMPLE 386 2- (1-Dimethylsulfamoyl-4-phenyl-piperidin-4-yl)- N- (2-methoxy-phenyl)-acetamide Synthesis

Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS/ 325 (M+H) +.

Title Compound: 2- (1-Dimethylsulfamoyl-4-phenyl-piperidin-4-yl)-N- (2- methoxy-phenyl) -acetamide was prepared using methodology described in Example 16. LRMS m/z 432 (M+H) +.

EXAMPLE 387 2- (l-Cyano-4-phenyl-piperidin-4-yl)-N- (2-methoxy-phenyl)-acetamide Synthesis Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS/ 325 (M+H) +.

Title Compound: 2- (1-Cyano-4-phenyl-piperidin-4-yl)-N- (2-methoxy- phenyl) -acetamide may prepared using methodology described in Example 521 using cyanogen bromide instead of 2-chloropyrimidine.. LRMS 350 (M+H) +.

EXAMPLE 388

2- [1- (2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidin-4-yl]-<BR&g t; N- (2-methoxy-phenyl)-acetamide Synthesis

Compound 1: Compound 1 was prepared using methodology described in Example 324. LRMS/ 325 (M+H) +.

Title Compound : 2- e (2-Methoxy-ethylsulfamoyl)-4-phenyl-piperidin-4-yl]- N- (2-methoxy-phenyl)-acetamide was prepared using methodology described in Example 17. LRMS nzlz 462 (M+H) +.

EXAMPLE 389 Example 389 was prepared using methodology described in Example 388. Example Structure Name M+H 389. \ o"3 N- (2-Methoxy-phenyl)-2- (4-phenyl- 447 1-propylsulfamoyl-piperidin-4-yl)- acetamid zizi IN HO CHs

EXAMPLE 390 4-benzyl-1- (3-phenyl-propionyl)-piperidine-4-carboxylic acid benzylamide Synthesis

Compound 1: Compound 1 is commercially available.

Compound 2: A solution of compound 1 (0.86 g; 2.7 mmol) in tetrahydrofuran (25 mL) was treated with triethylamine (0.49 mL; 3.7 mmol) and benzotriazol-l-yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.3 g; 2.9 mmol). After 0.5 h benzylamine (0.33 mL ; 3.0 mmol) was added and the reaction mixture was heated to 50°C for 15 h. The tetrahydrofuran was removed by evaporation and the residue was portioned between ethyl acetate and 5% aqueous hydrochloric acid. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. Column chromatography on silica gel using 1: 1 hexane: ethyl acetate as the eluent gave 0. 81 g of compound 2 as a colorless oil. LRMS m/z 410 (M+H) +.

Compound 3: A solution of compound 2 (0.41 g; 1.0 mmol) in dichloromethane (15 mL) was treated with trifluoroacetic acid (2 mL) at room temperature. After 24 h additional dichloromethane (50 mL) and 1 N sodium hydroxide (40 mL) was added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give compound 3 that was used in the next step without additional purification. LRMS mlz 309 (M+H) +.

Title Compound: A solution of compound 3 (0.16 g; 0.52 mmol) in tetrahydrofuran (20 mL) was treated with triethylamine (0.09 mL; 0.65 mmol) and hydrocinnamoyl chloride (0.1 g; 0.59 mmol) at room temperature. After 16 h the tetrahydrofuran was removed by evaporation and the residue was portioned between ethyl acetate and 5% aqueous hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride, dried (anhydrous sodium sulfate) and concentrated. Column chromatography on silica gel using 1: 1 hexane: ethyl acetate as the eluent gave 0.15 g of 4-benzyl-1- (3-phenyl-propionyl)-piperidine-4-carboxylic acid benzylamide as a white solid. LRMS mAz 442 (M+H) +.

EXAMPLE 391 4- (2-Fluoro-benzyl)-1- [3- (4-fluoro-phenyl)-propionyl]-piperidine- 4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide Synthesis F F C02H C02H Br OH OH BOC20 N dioxane N N H sat. NaHC03 LDA 0 1 2 3 1 tuf 3 F o r \ F o/\ Nu2 H TFA H N CH2C'2 N N Et3 5 THF 4 4 F 0 cl O/\ N HOH ¢X ; H F N BOP WF NEt3 THF

Compound 1: Compound 1 is commercially available.

Compound 2: Di-tert-butyl dicarbonate (12.66 g, 58.0 mmol) was added to a solution of piperidine-4-carboxylic acid (5.00 g, 38.7 mmol) in dioxane (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and stirred at room temperature for 48 h. The reaction mixture was concentrated to 100 mL under reduced pressure and ethyl acetate (200 mL) was added. The solution was made acidic with 6M hydrochloric acid (pH = 3), the organic layer collected and concentrated under reduced pressure to give 7.22 g of piperidine-1, 4-dicarboxylic acid mono-tert-butyl ester. LRMS milz 228. 1 (M-H)-.

Compound 3: Lithium diisopropylamide (10.9 mmol, 2M tetrahydrofuran) was added to a solution of piperidine-1, 4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.36 mmol) in tetrahydrofuran (25 mL) at 0 °C. After 1.5 h 2-fluorobenzyl bromide (0.788 mL, 6.54 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with the addition of water (10 mL) followed by 1M hydrochloric acid (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL), the organic layers collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.330 g, (22 %) of 4- (2-fluoro-benzyl)-piperidine-1, 4- dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CD3Cl3, 300 MHz) 8 7.11-7. 00 (m, 5H), 4.00 (br. , 2H), 2.92 (s, 2H), 2.90 (br. , 2H), 2.05 (br. , 2H), 1.46 (br. , 2H), 1.44 (s, 9H).

Compound 4: Benzotriazol-l-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.650 g, 1.47 mmol) was added to a solution of 2- (4-ethyl- phenyl) -ethylamine (0.235 mL, 1.47 mmol), 4- (2-fluoro-benzyl)-piperidine-1, 4- dicarboxylic acid mono-tert-butyl ester (0.330 g, 0.978 mmol) and triethylamine (0.409 mL, 2.93 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2 x 10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.301 g (65 %) of 4- [2- (4-ethyl-phenyl)-ethylcarbamoyl]-4- (2-fluoro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester. LRMS nzlz 469.1 (M+H) +.

Compound 5: Trifluoroacetic acid (20 mL) was added to a solution 4- [2- (4- ethyl-phenyl)-ethylcarbamoyl]-4- (2-fluoro-benzyl)-piperidine-1-carboxylic acid tert- butyl ester (0.300 g, 0.64 mmol) in dichloromethane (50 mL). After 1 h the reaction mixture was concentrated under reduced pressure, the crude product taken up in 1M sodium hydroxide (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.188 g (80 %) of 4- (2-fluoro-benzyl)-piperidine- 4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide LRMS iii/z 369.1 (M+H) +.

Title Compound: Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.266 g, 0.602 mmol) was added to a solution of 4- (2-fluoro- benzyl) -piperidine-4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide (0.185 g, 0.502 mmol), 3- (4-fluoro-phenyl)-propionic acid (0.101 g, 0.602 mmol) and triethylamine (0.210 mL, 1.51 mmol) in tetrahydrofuran (5 mL). After 1 h the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2 x 10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product purified by column chromatography to give 0.105 g (40 %) of 4- (2-fluoro-benzyl)-1- [3- (4-fluoro-phenyl)-propionyl]-piperidine-4- carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide LRMS m/z 519.2 (M+H) +.

EXAMPLE 392 4-Benzyl-1- (4-fluoro-benzenesulfonyl)-piperidine-4-carboxylic acid benzylamide Synthesis o _ 2 \\- tN69 1 X, PS-DIEA, MeCN t _/g H H 1-F In 'N O=S H 1 2. PS-trisamine o4F 1 F

Compound 1: Compound 1 was prepared as described in Example 390.

Title Compound: 4-Benzyl-l- (4-fluoro-benzenesulfonyl)-piperidine-4- carboxylic acid benzylamide was prepared using methodology described in Example 95. LRMS 467 (M+H) +.

EXAMPLES 393 TO 520 Examples 393 to 530 were synthesized using methodology described in Example 391 and Example 392. Example Structure Name M+H 393 ° g+ 4-Benzyl-4-benzylcarbamoyl-444 N piperidine-1-carboxylic acid benzyl ester N N 394 0 4-Benzyl-1- (2-phenoxy-acetyl)- 444 piperidine-4-carboxylic acid benzylamide Y N 395 0 4-Benzyl-l- (3-phenyl-acryloyl)- 440 C N < piperidine-4-carboxylic acid benzylamide N 0v Example Structure Name M+H 396 0 4-Benzyl-l-phenylacetyl-428 0//piperidine-4-carboxylic acid H benzylamide 0 O 397 0 / l-Benzoyl-4-benzyl-piperidine-4-414 carboxylic acid benzylamide N N Ui 398 ° + 4-Benzyl-l-propionyl-piperidine-4-365 carboxylic acid benzylamide cul- Y N 0 4-Benzyl-l- (2-benzyloxy-acetyl)- 458 piperidine-4-carboxylic acid H benzylamide i N 400 o/=\ 4-Benzyl-4-(4-fluoro-428 N benzylcarbamoyl)-piperidine-l- H carboxylic acid tert-butyl ester YH, oAol% H3 0 0 CH3 401 0-4-Benzyl-4- (3-trifluoromethyl- 478 N benzylcarbamoyl)-piperidine-l- H F F F carboxylic acid tert-butyl ester CN C F F t xH0H3 J ! -L'n3 O'O CH3 l 402 0 4-Benzyl-l- (3-phenyl-propionyl)- 510 piperidine-4-carboxylic acid 3- H F F F trifluoromethyl-benzylarnide F F N Example Structure Name M+H 403 0 4-Benzyl-l- [3- (2-chloro-phenyl)- 544 propionyl]-piperidine-4-carboxylic -F acid 3-trifluoromethyl-benzylamide F F 01 ci 404 Q/\ 4-Benzyl-l- (4-fluoro-benzyl)- 486 N piperidine-4-carboxylic acid 3- H F trifluoromethyl-benzylamide N N 405 0 4-Benzyl-l- (3-phenyl-propionyl)- 460 N piperidine-4-carboxylic acid 4- H fluoro-benzylamide J' 0-Y N 406 0 4-Benzyl-l- [3- (2-chloro-phenyl)- 494 N propionyl]-piperidine-4-carboxylic H acid 4-fluoro-benzylamide r N ci 407 0 4-Benzyl-l- [3- (4-methoxy-phenyl)- 540 N propionyl]-piperidine-4-carboxylic tNj H F acid 3-trifluoromethyl-benzylamide N O' Y, CH3 408 0 4-Benzyl-l- [3- (4-trifluoromethyl- 578 XN v phenyl)-propionyl]-piperidine-4- F carboxylic acid 3-trifluoromethyl- N benzylamide F F F F Example Structure Name M+H 409 0-4-Benzyl-1- [3- (3, 4-difluoro- 546 wN S phenyl)-propionyl]-piperidine-4- F carboxylic acid 3-trifluoromethyl- benzylarnide F F 410 0 4-Benzyl-l- [3- (4-fluoro-phenyl)- 526 ¢<N v acryloyl]-piperidine-4-carboxylic tNS H FF acid 3-trifluoromethyl-benzylamide F F N F 411 4-Benzyl-1- (4-fluoro-benzoyl)- 500 N piperidine-4-carboxylic acid 3- H F trifluoromethyl-benzylamide F F N Ola 412 0 4-Benzyl-l- [2- (4-chloro-phenoxy)- 546 acetyll-piperidine-4-carboxylic H acid 3-trifluoromethyl-benzylamide N F F OO w 'CL 413 0 F 4-Benzyl-1- [3- (4-methoxy-phenyl)- 490 vN < propionyl]-piperidine-4-carboxylic H acid 4-fluoro-benzylamide N o0 CH3 414'-F 4-Benzyl-l- [3- (4-trifluoromethyl- 528 N phenyl)-propionyll-piperidine-4- H carboxylic acid 4-fluoro- N benzylamide " F Example Structure Name M+H 415 0-F 4-Benzyl-1- [3- (3, 4-difluoro- 496 w NX phenyl)-propionyl]-piperidine-4- carboxylic acid 4-fluoro- benzylamide F F 416 0-F 4-Benzyl-1- (3-phenyl-propynoyl)- 456 N piperidine-4-carboxylic acid 4- H fluoro-benzylamide 0R C i 417 0 4-Benzyl-l- (4-fluoro-benzoyl)- 450 N piperidine-4-carboxylic acid 4- H fluoro-benzylamide N F 418 0 4-Benzyl-l- [2- (4-chloro-phenoxy)- 496 N acetyl]-piperidine-4-carboxylic H acid 4-fluoro-benzylamide N 00. vCI 419 F 4-Benzyl-l- (4-methoxy- 498 nua benzenesulfonyl)-piperidine-4- carboxylic acid 4-fluoro- IN benzylamide off z 6H, 420 0 4- (4-Fluoro-benzyl)-l- (3-phenyl- 528 I w N I w propionyl)-piperidine-4-carboxylic H acid 3-trifluoromethyl-benzylamide F-0 e N rif i Example Structure Name M+H 421 0 1- (4-fluoro-benzenesulfonyl)-4- (4- 554 N fluoro-benzyl)-piperidine-4- F H carboxylic acid 3-trifluoromethyl- benzylamide O, I F F F F 422 0 4- (4-Fluoro-benzyl)-4- 442 phenethylcarbamoyl-piperidine-l- F N carboxylic acid tert-butyl ester N, ozon 423 tN 4- [2- (4-Ethyl-phenyl)- 470 ethylcarbamoyl]-4- (4-fluoro- N benzyl)-piperidine-l-carboxylic acid tert-butyl ester 424 0 4- (4-Fluoro-benzyl)-l- (3-phenyl- 474 propionyl)-piperidine-4-carboxylic H acid phenethyl-amide f N 425 o 4- (4-Pluoro-benzyl)-l- (2-phenoxy- 476 acetyl)-piperidine-4-carboxylic F H acid phenethyl-amide F N OO w i 426 1- (4-Fluoro-benzenesulfonyl)-4- (4- 500 fluoro-benzyl)-piperidine-4- F H carboxylic acid phenethyl-amide F N F F 427 o ~CH3 4-(4-Fluoro-benzyl)-1-(3-phenyl-502 N propionyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- N [ (Y p Y) Y o amide k 428 o ~tf CH3 4-(4-Fluoro-benzyl)-1-(2-phenoxy-504 N acetyl)-piperidine-4-carboxylic F). J J H N acid [2- (4-ethyl-phenyl)-ethyl]- amide Example Structure Name M+H 429 o vCH3 1-(4-Fluoro-benzenesulfonyl)-4-(4-528 fluoro-benzyl)-piperidine-4- F H carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide F 430 XCH3 1-Benzenesulfonyl-4-benzyl-492 o, \ piperidine-4-carboxylic acid [2- (4- XH ethyl-phenyl)-ethyl]-amide H IN crs 431 CH3 4-Benzyl-l- (toluene-4-sulfonyl)- 506 0 piperidine-4-carboxylic acid [2- (4- CH ethyl-phenyl)-ethyl]-amide H ion CH3 432-CH3 4-Benzyl-l- (4-fluoro- 510 benzenesulfonyl)-piperidine-4- ¢<H carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide Is F 433YCHg 4-Benzyl-l- (4-methoxy-522 o benzenesulfonyl)-piperidine-4- H carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide OvSn, l ° vo, CH3 4-Benzyl-l- (4-chloro- 526 kNw benzenesulfonyl)-piperidine-4- CX H carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide IN s cl 435 VCH3 4-Benzyl-1-(4-trifluoromethoxy-576 o NJU benzenesulfonyl)-piperidine-4- N carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide s F 'lao F O Example Structure Name M+H 436 c 4-Benzyl-l- [2- (4-fluoro-phenyl)- 488 o ~W acetyl]-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- XN) F amide oW 0 437 CH3 4-Benzyl-l- (4-chloro-benzoyl)- 490 o ~\ piperidine-4-carboxylic acid [2- (4- XN ethyl-phenyl)-ethyl]-amide N N ots ci 438 CCH3 4-Benzyl-1-(2-phenyl-496 cyclopropanecarbonyl)-piperidine- N 4-carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide oH 439 H3 4-Benzyl-l- [2- (4-methoxy-phenyl)- 500 o ~\ acetyl]-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- amide L J o amide N i O, CH3 oW o 440 c 4-Benzyl-1- [2- (4-chloro-phenyl)- 504 acetyl]-piperidine-4-carboxylic VN acid [2- (4-ethyl-phenyl)-ethyl]- 'ir ci amide jCr o 441 4-Benzyl-l- (3-phenyl-propionyl)- 486 0 piperidine-4-carboxylic acid [2- (2- N o methoxy-phenyl)-ethyl]-aniide °'r, N O' Y \ i 442 » gbr 4-Benzyl-1-(3-phenyl-propionyl)-535 piperidine-4-carboxylic acid [2- (4- M N bromo-phenyl)-ethyl]-amide ß) H N 0 Example Structure Name M+H 443 H3 4-Benzyl-l- (3-phenyl-propionyl)- 470 piperidine-4-carboxylic acid (2-p- o tolyl-ethyl)-amide N N W 444 CH3 4-Benzyl-l- (3-phenyl-propionyl)- 516 piperidine-4-carboxylic acid [2- (2, 5-dimethoxy-phenyl)-ethyl]- amide N 10 N O N N 445 0) 4-Benzyl-1- (3-phenyl-propionyl)- 500 o piperidine-4-carboxylic acid (2- N benzo [1, 3] dioxol-5-yl-ethyl)-amide N p N 446 ci 4-Benzyl-l- (3-phenyl-propionyl)- 525 o vCI piperidine-4-carboxylic acid [2- ¢X>N (3, 4-dichloro-phenyl)-ethyl]-amide - 0" N C\\ 447/CH3 4-Benzyl-l- (3-phenyl-propionyl)- 484 piperidine-4-carboxylic acid [2- (2, 4-dimethyl-phenyl)-ethyl]-amide 0" H 01, Example Structure Name M+H (3-phenyl-propionyl)-484 o /-CH3 piperidine-4-carboxylic acid [2- N (3, 4-dimethyl-phenyl)-ethyl]-amide . CN H N I N k 449 4-Benzyl-l- (3-phenyl-propionyl)- 470 0 piperidine-4-carboxylic acid (2-o- < H tolyl-ethyl)-amide N N i 450 4-Benzyl-l- (3-phenyl-propionyl)- 470 ONK ~~ 3 piperidine-4-carboxylic acid (2-m- EN tolyl-ethyl)-amide Y p o 451 CH3 4-Benzyl-1-(3-phenyl-propionyl)-512 /- piperidine-4-carboxylic acid (3- H methyl-benzo [b] thiophen-2- N J ylmethyl)-amide i N 452 4-Benzyl-l- (3-phenyl-propionyl)- 490 O piperidine-4-carboxylic acid [2- (4- chloro-phenyl)-ethyl]-amide N . N p N 453 CH3 4-Benzyl-l- (3-phenyl-propionyl)- 484 piperidine-4-carboxylic acid [2- (4- N ethyl-phenyl)-ethyl]-amide N N i Example Structure Name M+H 454 F 4-Benzyl-l- (3-phenyl-propionyl)- 524 piperidine-4-carboxylic acid [2- (3- N trifluoromethyl-phenyl)-ethyl]- amide o N 455 Ct 4-Benzyl-l- (3-phenyl-propionyl)- 476 piperidine-4-carboxylic acid 2- H chloro-benzylan-lide N p i 456 4-Benzyl-l- (3-phenyl-propionyl)- 456 0 piperidine-4-carboxylic acid N phenethyl-amide H O i 457 H3 4-Benzyl-l- (5-methyl-3-phenyl- 537 0 isoxazole-4-carbonyl)-piperidine-4- /-N carboxylic acid [2- (4-ethyl- N CH3 phenyl)-ethyl]-amide P oxo r4 W} 458 F 4-Benzyl-1- (3-phenyl-propionyl)- 474 \ piperidine-4-carboxylic acid [2- (4- fluoro-phenyl)-ethyl]-amide zon N p-I w i 459 0 4-Benzyl-l- (3-phenyl-propionyl)- 470 piperidine-4-carboxylic acid (3- H phenyl-propyl)-amide o 0 Example Structure Name M+H 460 0 CH3 4-Benzyl-l- (3-phenyl-propionyl)- 456 N piperidine-4-carboxylic acid 3- H methyl-benzylaniide 0< i 461 0 4-Benzyl-l- (3-phenyl-propionyl)- 476 wH vCI piperidine-4-carboxylic acid 4- chloro-benzylamide N 09 462 4-Benzyl-l- (3-phenyl-propionyl)- 474 ° 0 piperidine-4-carboxylic acid [2- (2- N F fluoro-phenyl)-ethyl]-amide CN H p i 463 4-Benzyl-1- (3-phenyl-propionyl)- 474 0 F piperidine-4-carboxylic acid [2- (3- N fluoro-phenyl)-ethyl]-amide N p N 464 CH3 4-Benzyl-l- (2-methoxy-acetyl)- 424 0 piperidine-4-carboxylic acid [2- (4- t\ N ethyl-phenyl)-ethyl]-amide N O4osCH3 465 XCH3 1-Benzoyl-4-benzyl-piperidine-4-456 kNv carboxylic acid [2- (4-ethyl- < H phenyl)-ethyl]-amide Y N 0 ;- 466 c 4-Benzyl-l-phenylacetyl-470 9 ~ piperidine-4-carboxylic acid [2- (4- XH ethyl-phenyl)-ethyl]-amide N n IX) 0 Example Structure Name M+H 467 YCHa 4-Benzyl-l- (4-methyl-benzoyl)- 470 piperidine-4-carboxylic acid [2- (4- XH ethyl-phenyl)-ethyl]-amide I N ou CH3 468 H3 4-Benzyl-l- (4-fluoro-benzoyl)- 474 o ~\ piperidine-4-carboxylic acid [2- (4- X H ethyl-phenyl)-ethyl]-amide H N p I w F 469 CH3 4-Benzyl-l- (2-phenoxy-acetyl)- 486 ° _9 piperidine-4-carboxylic acid [2- (4- XN ethyl-phenyl)-ethyl]-amide y N N 470 CH3 4-Benzyl-l-cyclohexanecarbonyl-462 piperidine-4-carboxylic acid [2- (4- N ethyl-phenyl)-ethyl]-amide H oX 471 fA^CH3 4-Benzyl-l-(isoxazole-5-carbonyl)-447 °, S piperidine-4-carboxylic acid [2- (4- VH ethyl-phenyl)-ethyl]-amide Y N 0 472 XCH3 4-Benzyl-1-(2, 4, 5-trifluoro- 510 o benzoyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- amide N F F I F 473 "CHs 4-Benzyl-l-but-2-enoyl-piperidine-420 o, 2 4-carboxylic acid [2- (4-ethyl- fV"N phenyl)-ethyl]-amide H N OJCH3 Example Structure Name M+H 474 YCHs 4-Benzyl-l-pentanoyl-piperidine-4-436 o carboxylic acid [2- (4-ethyl- < H phenyl)-ethyl]-amide N Y oS CH3 475/"'4-Benzyl-l- (3-methyl-butyryl)- 436 0 piperidine-4-carboxylic acid [2- (4- XH ethyl-phenyl)-ethyl]-amide "0 N CH3 SlCHa 476 ; -°"3 1-Acetyl-4-benzyl-piperidine-4-394 0 carboxylic acid [2- (4-ethyl- N phenyl)-ethyl]-amide N O>CHa 477 (Y"°"'4-Benzyl-l- (pyridine-4-carbonyl)- 457 piperidine-4-carboxylic acid [2- (4- N ethyl-phenyl)-ethyll-amide O4q N con , N 478 AcHa 4-Benzyl-1-(pyridine-2-carbonyl)-457 p piperidine-4-carboxylic acid [2- (4- N ethyl-phenyl)-ethyl]-amide H N p 479/"° 4-Benzyl-l- (pyridine-3-carbonyl)- 457 piperidine-4-carboxylic acid [2- (4- X N ethyl-phenyl)-ethyl]-amide "0 N O I N 480 CH3 4-Benzyl-l- (2-chloro-pyridine-3- 491 carbonyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- amide ci ole Example Structure Name M+H 481 <Y 4-Benzyl-l- (3-piperidin-l-yl- 491 ° _ propionyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- H amide N oN 482 Y'4-Benzyl-l- (lH-indole-2- 495 carbonyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- J amide N 483 Y 4-Benzyl-l- (3-phenyl-propynoyl)- 480 o < piperidine-4-carboxylic acid [2- (4- tH ethyl-phenyl)-ethyl]-amide < N 484 XcHs 4-Benzyl-1-(3-pyridin-3-yl-485 , > propionyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- amide Y 0-'l N 485 Y 4-BenzyI-l- [2- (l-methyl-lH-474 imidazol-4-yl)-acetyl]-piperidine- N 4-carboxylic acid [2- (4-ethyl- pH3 phenyl)-ethyll-amide N N 486 CCH3 4-Benzyl-1-(6-methyl-pyridine-3-471 carbonyl)-piperidine-4-carboxylic XH acid [2- (4-ethyl-phenyl)-ethyl]- amide N aha Example Structure Name M+H 487 vCH3 4-Benzyl-1-(2-dimethylamino-437 o acetyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- amide N CH3 0S\/NsCH 488 Y 4-Benzyl-l- (lH-indazole-3- 496 ° > carbonyl)-piperidine-4-carboxylic XH acid [2-(4-ethyl-phenyl)-ethyl]- N amide Cl N 489 XCH3 4-Benzyl-1-(pyrazine-2-carbonyl)-458 piperidine-4-carboxylic acid [2- (4- ¢< HN ethyl-phenyl)-ethyl]-amide "0 Y o-'-N N' 490/°"'4-Benzyl-l- (morpholine-4- 465 O) S carbonyl)-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- amide amide N k-o 491 | CH3 4-Benzyl-1-(2-oxo-imidazolidine-464 lc) 4-carbonyl)-piperidine-4- N carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide ogNx N N H H 492 4-Benzyl-l- (lH-pyrazole-4- 446 carbonyl)-piperidine-4-carboxylic XHN acid [2-(4-ethyl-phenyl)-ethyl]- amide Y ""C- N Example Structure Name M+H 493 CH3 4-Benzyl-l- ( [1, 2, 3] thiadiazole-4- 464 o Jv carbonyl)-piperidine-4-carboxylic XN~ acid [2-(4-ethyl-phenyl)-ethyl]- 'amide amide os non NN 494 f °"3 4-Benzyl-1- [3- (4-chloro-phenyl)- 518 0 propionyl]-piperidine-4-carboxylic N acid [2- (4-ethyl-phenyl)-ethyl]- 'amide I """tu /CI 495 l- (lH-Benzoimidazole-5- 496 carbonyl)-4-benzyl-piperidine-4- N carboxylic acid [2- (4-ethyl- 'phenyl)-ethyl]-amide N O N H 496/ wCH3 4-Benzyl-l- (l-cyano- 445 cyclopropanecarbonyl)-piperidine- N 4-carboxylic acid [2- (4-ethyl- phenyl)-ethyl]-amide 0f N 497 ci 4-Benzyl-l- (3-phenyl-propionyl)- 584 piperidine-4-carboxylic acid [2- (4- 0 N chloro-phenyl)-ethyl]- (1-methyl- L",, r\ 1H-imidazol-2-ylmethyl)-amide J DUS N du 1 498 °'4-Benzyl-1- (4-fluoro-benzoyl)- 574 piperidine-4-carboxylic acid [2- (4- chloro-phenyl)-ethyl]- (l-methyl- cor 1H-imidazol-2-ylmethyl)-amide N/ CH, O Y \ CH3 Example Structure Name M+H 499 Cl 4-Benzyl-l-phenylacetyl-570 piperidine-4-carboxylic acid [2- (4- o ß chloro-phenyl)-ethyl]- (l-methyl- 1H-imidazol-2-ylmethyl)-amide /jan N CH3 ou 500 4-Benzyl-l- (2-phenoxy-acetyl)- 586 piperidine-4-carboxylic acid [2- (4- o N chloro-phenyl)-ethyl]- (l-methyl- IH-imidazol-2-ylmethyl)-amide ,,, N 0 CH3 \ 501 HCI 4-Benzyl-1- [2-(4-chloro-phenoxy)-621 acetyl]-piperidine-4-carboxylic 0 N acid [2- (4-chloro-phenyl)-ethyl]- (l- C XN) methyl-lH-imidazol-2-ylmethyl)- NJ amide 0 C (H3 I ci 'CI 502 XCl 1-Acetyl-4-benzyl-piperidine-4-494 carboxylic acid [2- (4-chloro- N phenyl)-ethyl]- (I-methyl-IH- N imidazol-2-ylmethyl)-amide N CH3 O CH3 503 ci 4-Benzyl-1-cyclohexanecarbonyl-562 piperidine-4-carboxylic acid [2- (4- 8> SN~ chloro-phenyl)-ethyl]-(l-methyl- -N Nl 1H-imidazol-2-ylmethyl)-amide N N D/ J CHUS O'j 1 Example Structure Name M+H 504 ° 4-Benzyl-1- (3-methyl-butyryl)- 536 piperidine-4-carboxylic acid [2- (4- o n SN~ chloro-phenyl)-ethyl]-(l-methyl- N 1H-imidazol-2-ylmethyl)-amide N CH3 N 3 OvCH3 505 4-Benzyl-l- (isoxazole-5-carbonyl)- 547 piperidine-4-carboxylic acid [2- (4- 0 N chloro-phenyl)-ethyl]- (l-methyl- 1H-imidazol-2-ylmethyl)-amide N JAN CH3 i chu O-N 506 4-Benzyl-l- (2-methoxy-acetyl)- 524 piperidine-4-carboxylic acid [2- (4- o i N chloro-phenyl)-ethyl]- (l-methyl- 9° t) lH-imidazol-2-ylmethyl)-amide N N N 04 sCH3 507 wCI l-Benzenesulfonyl-4-benzyl-592 piperidine-4-carboxylic acid [2- (4- N chloro-phenyl)-ethyl]- (l-methyl- t/N IH-imidazol-2-ylmethyl)-amide 0v119 I CH3 eli-- / 508 ci 4-Benzyl-l- (4-fluoro- 610 benzenesulfonyl)-piperidine-4- o r4/-o carboxylic acid [2- (4-chloro- phenyl)-ethyl]- (l-methyl-1H- N imidazol-2-ylmethyl)-amide S CH3 OII I \ O clt 509 ° l- [3- (4-Fluoro-phenyl)-propionyl]- 532 4- (4-methoxy-benzyl)-piperidine- 0 4-carboxylic acid [2- (4-ethyl- - phenyl)-ethyl]-amide Nu F j° frr , JU Example Structure Name M+H 510"y 4- (3-Chloro-benzyl)-l- [3- (4- 536 fluoro-phenyl)-propionyl]- piperidine-4-carboxylic acid [2- (4- ethyl-phenyl)-ethyl]-araide 9 H I F EXAMPLE 521

4-Benzyl-1-pyrimidin-2-yl-piperidine-4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide Synthesis Compound 1: Compound 1 was prepared using methodlogy described in Example 390. LRMS nilz 352 (M+H) +.

Title Compound: A solution of compound 1 (0.05 g; 0.14 mmol) in anhydrous acetonitrile (1 mL) was treated with 2-chloropyrimidine (0.024 g; 0.21 mmol) and diisopropyl ethylamin (0.036 mL ; 0.21 mmol) and heated at 90°C for 1 h.

The acetonitrile was removed by evaporation and the crude residue was purified by

preparative HPLC to give 4-benzyl-1-pyrimidin-2-yl-piperidine-4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide as a white solid. LRMS m/z 430 (M+H) +.

EXAMPLE 522 4-Benzyl-l-dimethylsulfamoyl-piperidine-4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide Synthesis Compound 1: Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H) +.

Title Compound : 4-Benzyl-l-dimethylsulfamoyl-piperidine-4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide was prepared using methodology described in Example 16. LRMS nilz 458 (M+H) +.

EXAMPLE 523 Example 523 was prepared using methodology described in Example 522. Example Structure Name M+H 523 <'4-Benzyl-1-dimethylsulfamoyl-559 piperidine-4-carboxylic acid [2- (4- o S \ kN~ chloro-phenyl)-ethyl]-(l-methyl- 1H-imidazol-2-ylmethyl)-amide ND/ o=t=o CHs O=S=O I C2sCH3

EXAMPLE 524

4-Benzyl-l- (2-methoxy-ethylsulfamoyl)-piperidine-4-carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide

Compound 1: Compound 1 was prepared using methodology described in Example 390. LRMS m/z 352 (M+H) +.

Title Compound: 4-Benzyl-1-(2-methoxy-ethylsulfamoyl)-piperidine-4- carboxylic acid [2- (4-ethyl-phenyl)-ethyl]-amide was prepared using methodology described in Example 17. LRMS m/z 488 (M+H) +.

EXAMPLES 525 TO 526 Examples 525 to 526 were prepared using methodology described in Example 524.

Example S tructure Name M+H 525 0 CH3 4-Benzyl-l-benzylsulfamoyl-521 piperidine-4-carboxylic acid [2- (4- ethyl-phenyl)-ethyl]-amide HA HN 526 0 CH3 4-Benzyl-l- (4-fluoro- 539 N benzylsulfamoyl)-piperidine-4- carboxylic acid [2- (4-ethyl- °= 1s-° phenyl)-ethyl]-amide HN F EXAMPLE 527 1- [4- (isoquinolin-1-ylaminomethyl)-4-phenyl-piperidin-1-yl]- 3-phenyl-propan-1-one Synthesis ci i 1 I N , NH2// N H 2 Pd (OH) 2 N Pd (OAc) 2 2- (di-t-butylphosphino)-N biphenyl NaOtBu toluene 2

Compound 1: A suspension of l-benzyl-4-phenyl-piperidine-4-carbonitrile (6.24 g; 20 mmol) in tetrahydrofuran was cooled to 0°C and treated with lithium aluminum hydride (3.04g ; 80 mmol). The reaction mixture was allowed slowly warm to room temperature overnight. The reaction was cooled in an ice-acetone bath and quenched with water (12 mL) and 15% aqueous sodium hydroxide (3 mL). The resulting slurry was filtered through celite eluting with ethyl ether and evaporated to give 4.51 g of compound 1 as a colorless oil that was used in the next step without additional purification. LRMS m/z 281 (M+H) +.

Compound 2: Pd (OAc) 2 (4.5 mg, 0.02 mmol), 2- (di-t- butylphosphino) biphenyl (11.9 mg, 0.04 mmol) and sodium t-butoxide (0.54 g, 5.6 mmol) were added to toluene (8 mL) and the mixture was sparged with argon. 1- Chloroisoquinoline (0.65 g, 4 mmol) and compound 1 (1.35 g, 4.8 mmol) were added and the reaction was heated at reflux under an argon atmosphere. After 48 hours a second portion of Pd (OAc) 2 (4.5 mg, 0.02 mmol) and- (di-t-butylphosphino) biphenyl (11.9 mg, 0.04 mmol) was added. The reaction was allowed to reflux another 24 hours then diluted with water (8 mL). The mixture was filtered through celite pad and

portioned between ethyl acetate and water. The organic phase was separated, dried (anhydrous magnesium sulfate), filtered and concentrated. Column chromatography on silica gel using a dichloromethane to ethyl acetate gradient as the eluent gave 0.29 g compound 2. LRMS m/z 408 (M+H) +.

Compound 3: A solution of compound 2 (0.250g) in methanol (20 mL) was treated with Pd (OH) 2 (50 mg), placed under at atmosphere of hydrogen (60 psi) and heated to 40°C until no starting material remained as judged by LCMS. The reaction mixture was filtered through celite using ethyl acetate as the eluent and evaporated to give 0.19 g compound 3 that was used in the next step without further purification.

LRMS m/z 318 (M+H) +.

Title Compound: 1- [4-(isoquinolin-1-ylaminomethyl)-4-phenyl-piperidin-1- yl]-3-phenyl-propan-1-one was prepared using methodology described in Example 390. LRMS m/z 451 (M+H) +.

EXAMPLE 528 [1- (4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-ylmethyl]- isoquinolin-1-yl-amine Synthesis 1 1 so2cl N XHS3 1. FJ3, PS-DIEA, MeCN X Nt C\ J _H H N 2. PS-trisamine N H H 1 s F

Compound 1: Compound 1 was prepared as described in Example 527.

Title Compound : [1- (4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4- ylmethyl]-isoquinolin-l-yl-amine was prepared using methodology described in Example 95.. LRMS into 477 (M+H) +.

EXAMPLE 529 Isoquinolin-1-yl- (4-phenyl-1-pyrimidin-2-yl-piperidin-4-ylmethyl)-amine Synthesis Compound 1: Compound 1 was prepared as described in Example 527.

Title Compound : Isoquinolin-1-yl-(4-phenyl-1-pyrimidin-2-yl-piperidin-4- ylmethyl) -amine was prepared using methodology described in Example 521. LRMS m/z 396 (M+H) +.

EXAMPLE 530

Synthesis Compound 1: Compound 1 was prepared as described in Example 527. Compound 2: Compound 2 was prepared using methodology described in Example 25. LRMS mlz 463 (M+H) +.

Title Compound: The title compound was prepared using methodology described in Example 25. LRMS i-nlz 413 (M+H) +.

EXAMPLE 531 4- (Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidine- 1-sulfonic acid dimethylamide Synthesis _ _ \ I N , \ I N 1) UH3) 2NS02CI N THF, Ps-DIEA N H 1 2) AP-Trisamine O=S=O N

Compound 1: Compound 1 was prepared as described in Example 527.

Title Compound : 4- (Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidine-1- sulfonic acid dimethylamide was prepared using methodology described in Example 16. LRMS m/z 426 (M+H) +.

EXAMPLE 532

4- (Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidine-.

1-sulfonic acid benzylamide Synthesis

Compound 1: Compound 1 was prepared as described in Example 527. Title Compound : 4- (Isoquinolin-1-ylaminomethyl)-4-phenyl-piperidine-1- sulfonic acid benzylamide was prepared using methodology described in Example 17.

LRMS nilz 488 (M+H) +.

EXAMPLE 533

1- [4-phenyl-1- (3-phenyl-propionyl)-piperidin-4-ylmethyl]- 1, 3-dihydro-benzoimidazol-2-one Synthesis

Compound 1: Compound 1 was prepared as described in Example 527.

Compound 2: A mixture of compound 1 (0.60 g, 2.14 mmol), 2- fluronitrobenzene (0.25 mL, 2.35 mmol) and potassium carbonate (excess) in N, N- dimethylformamide, was stirred overnight at 70°C. The reaction was diluted with water (4 mL) then extracted with ethyl ether (4x15 mL). The combined extracts were evaporated and the residue was purified by column chromatography on silica gel using a dichloromethane to 1: 1 dichloromethane/ethyl acetate gradient. Product fractions were combined and evaporated to give 0.75 g (87%) compound 2. LRMS iiilz 403 (M+H) +.

Compound 3: Compound 2 (0.75 g, 1.87 mmol) was dissolved in methanol and a catalytic amount of 10% palladium/carbon was added. The mixture was stirred under H2 (balloon pressure) until the color disappeared. The reaction was filtered through a celite pad and evaporated to give 0.58 g (84%) of compound 3. LRMS n7/z 373 (M+H) +.

Compound 4: A solution of compound 3 (76.3 mg, 0.206 mmol) in dichloromethane (4 mL) was treated with triethylamine (63 jjL, 0.45 mmol) and a solution of diphosgene (13.7 pL, 0.113 mmol) in dichloromethane (2 mL). After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate and separated. The organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated. Column chromatography on silica gel using dichloromethane as the eluent gave 0.077g of compound 4. LRMS m/z 399 (M+H) +.

Compound 5: Compound 4 (63.1 mg, 0.159 mmol) was dissolved in methanol and Pd (OH) 2/C (wet) was added. The mixture was hydrogenated at 60 psi and 50°C overnight. The reaction was purified directly by column chromatography on silica gel using 59: 40: 1 methanol: chloroform: ammonium hydroxideas the eluent to give 10 mg (20%) of compound 5. LRMS nilz 508 (M+H) +.

Title Compound: 1- [4-phenyl-1- (3-phenyl-propionyl)-piperidin-4-ylmethyl]- 1, 3-dihydro-benzoimidazol-2-one was prepared using methodology described in Example 390. LRMS nVz 441 (M+H) +.

EXAMPLE 534 1- [1- (4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-ylmethyl]-&l t;BR> <BR> 2-methyl-1 H-benzoimidazole Synthesis

Compound 1: Compound 1 was prepared as described in Example 533.

Compound 2: A solution of compound 1 (0.2508 g, 0.676 mmol) in acetic acid (2 mL) was treated with EEDQ (0.170 g, 0.678 mmol) and heated to 120°C.

After 12 h, the reaction mixture was evaporated to dryness and the residue was portioned between ethyl acetate (4 mL) and saturated aqueous sodium bicarbonate (3 mL). The aqueous layers was separated and washed with dichloromethane (2 x 4 mL). The combined organic layers were combined, dried (anhydrous magnesium sulfate), filtered and concentrated. Column chromatography on silica gel using an ethyl acetate to 10% methanol: ethyl acetate gradient as the eluent gave 0.21 g of compound 2. LRMS m/z 397 (M+H) + Compound 3: Compound 3 was prepared using methodology described in Example 533. LRMS niz 306 (M+H) + Title Compound : 1- [1- (4-Fluoro-benzenesulfonyl)-4-phenyl-piperidin-4- ylmethyl]-2-methyl-lH-benzoimidazole was prepared using methodology described in Example 95. LRMS nilz 464 (M+H) + EXAMPLE 535

1- [4-(2-Methyl-benzoimidazol-1-ylmethyl)-4-phenyl-piperidin-1- yl]- 3-phenyl-propan-1-one Synthesis

Compound 1: Compound 1 was prepared as described in Example 534.

Title Compound : 1- [4- (2-Methyl-benzoimidazol-1-ylmethyl)-4-phenyl- piperidin-l-yl]-3-phenyl-propan-1-one was prepared using methodology described in Example 94. LRMS niz 439 (M+H) +.

EXAMPLE 536 Synthesis

Compound 1: Compound 1 was prepared as desribed in Example 534. Compound 2: Compound 2 was prepared using methodology described in Example 25. LRMS i7ilz 451 (M+H) +.

Title Compound: The title compound was prepared using methodology described in Example 25. LRMS mlz 402 (M+H) +.

EXAMPLE 537 Example 537 was prepared using methodology described in Example 536.

Example Structure Name M+H 537 N 464 N z H X N NON "-a N EXAMPLE 538

N- (4-Benzyl-piperidin-4-ylmethyl)-2-methoxy-benzamide Synthesis CN benzoylchloride N LDA, BnBr I--, N TEA/DCM 0+ THF N N N H p H1 2 3 X 1 2 3 0--l-C C J LAHTHF I LAH/T F O O N 1) chloroethyl r 1 H Wi chloroformate Q J Anisoylchloride Q J < p « N TEA/DCM N N 2) MeOH 5 4

Compound 1: Compound 1 is commercially available.

Compound 2: To compound 1 (1.0 g, 9.08 mmol) in dichloromethane (30 mL) at 0 ° C was added triethylamine (1.5 mL, 10.7 mmol) followed by benzoylchloride (1.1 mL, 9.08 mmol). The reaction mixture was stirred at room temperature for 3 h, diluted with ethyl ether (100 mL), washed with saturated 1 N HC1, 1 N NaOH, water and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromotography using Hexanes/EtOAc (2/1) as eluent to give a white solid compound 2,1. 41 g (73% yield).

LCMS Rt 1.06 min, [M+1] 215.2.

Compound 3: To a solution of diisopropylamine (0.35 mL, 2.52 mmol) in dry tetrahydrofuran (2.5 mL) at 0 °C was added 1.58 mL (2.52 mmol) of 1.6 M n- BuLi in hexanes. After 30 minutes, the reaction mixture was cooled to-78 ° C.

Compound 2 (360 mg, 1.68 mmol) in dry tetrahydrofuran (2.5 mL) was added dropwise. After 1 h, BnBr (0.22 mL, 1.85 mmol) was added. After stirring from-78 ° C to room temperature over 2 h the reaction mixture was quenched with water and diluted with Et20 (30 mL). The organic phase was washed with 1 N HC1, water and brine. The aqueous phase was extracted with CH2Cl2. The combined organic phase was dried over Anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromotography using Hexanes/EtOAc (1/4) as eluent to give a white solid compound 3,0. 472 g (92% yield). NMR 1H (CDC13) õ (ppm) 1.40-2. 05 (4 H, m), 2.89 (2 H, s), 3.00-3. 42 (2 H, m), 3.70-3. 90 (1 H, bs), 4.70-4. 90 (1 H, bs), 7.26-7. 43 (10 H, m).

Compound 4: To compound 3 in dry tetrahydrofuran (5 mL) was added 231 mg (mmol) of LAH then stirred at 65 °C for 20 h. The solution was cooled to 0 °C and quenched with water (0.23 mL), 15% NaOH (0.69 mL) and water (0.23 mL). The quenched reaction mixture was stirred at ambient temperature for 0.5 h. The solid was filtered and washed with Et2O. The organic solution was dried over Na2S04, filtered and concentrated to give a colorless oil compound 4 sufficiently pure to be taken on to the next step. LCMS [M+1] 295.2.

Compound 5: To compound 4 (1.52 mmol) in dichloromethane (5 mL) at 0 °C was added 0.43 mL (3.06 mmol) of Et3N followed by 0.25 mL (1.68 mmol) of o- anisoyl chloride. After stirring 2 hours from 0 °C to room temperature, the reaction mixture was diluted with Et20 (30 mL), washed with IN NaOH, water, sat. sodium chloride, dried over anh. sodium sulfate and concentrated. The residue was purified by silica gel chromatography using EtOAc as eluent to give a light yellow syrup compound 5,0. 551 g (85% yield). NMR 1H (CDC13) 8 (ppm) 1.45-2. 0 (4 H, m), 2.02-2. 70 (4 H, m), 2.69 (2 H, s), 3.40 (2 H, d, J= 5.9 Hz), 3.55 (2 H, s), 4.00 (2 H, s), 7.00 (1 H, d, J= 8.2 Hz), 7.08-7. 40 (12 H, m), 7.45 (1 H, dt, J= 1.7, 11.1 Hz), 8.05 (1 H, bs), 8.23 (1 H, dd, J=1.8, 7.8 Hz). LCMS Rt 1.72 min, [M+1] 429.2.

Title Compound: N- (4-Benzyl-piperidin-4-ylmethyl)-2-methoxy-benzamide was prepared using methodology described in Example 1. LCMS [M+1] 339. 1.

EXAMPLE 539 4-Benzyl-4- [(2-methoxy-benzoylamino)-methyl]-piperidine- 1-carboxylic acid ethyl ester Synthesis Compound 1: Compound 1 was prepared as described in Example 538.

Title Compound : 4-Benzyl-4- [ (2-methoxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. NMR 1H (CDC13) 8 (ppm) 1.24 (3 H, t, J= 7.1 Hz), 1.47-1. 51- (4 H, m), 2.70 (2 H, s), 3.41-3. 50 (4 H, m), 3.65-3. 72 (2 H, m), 4.01 (3 H, s), 4.11 (2 H, q, J= 7.1 Hz), 7.02 (1 H, d, J= 8.2 Hz), 7.09-7. 33 (6 H, m), 8.06 (1 H, bs), 7.48 (1 H, td, J= 1.7, 7.5 Hz), 8.22 (1 H, dd, J= 2.2, 7.8 Hz). LCMS Rt 1.72 min, [M+1] 411.1.

EXAMPLE 540

N- [4-Benzyl-1- (3-phenyl-propionyl)-piperidin-4-ylmethyl]-2-methoxy-benzami de Synthesis

Compound 1: Compound 1 was prepared as described in Example 538.

Title Compound : N-[4-Benzyl-1-(3-phenyl-propionyl)-piperidin-4- ylmethyl]-2-methoxy-benzamide was prepared using methodology described in Example 94. NMR 1H (CDC13) 6 (ppm) 1.26-1. 38 (2 H, m), 1.43-1. 50 (2 H, m), 2.59- 2.64 (2 H, m), 2.65 (2 H, s), 2.93-2. 98 (2 H, m), 3.23-3. 62 (5 H, m), 3.95-4. 05 (1 H, m), 4.01 (3 H, s), 7.02 (1 H, d, J= 8.2 Hz), 7.09-7. 34 (11 H, m), 7.45-7. 55 (1 H, m), 8.07 (1 H, t, J=5. 8Hz), 8.21 (1 H, dd, J=1. 8,7. 8 Hz).

LCMS Rt 1.77 min, [M+1] 471. 1.

EXAMPLE 541

N- [4-Benzyl-l- (4-fluoro-benzylsulfamoyl)-piperidin-4-ylmethyl]- 2-methoxy-benzamide Synthesis

Compound 1: Compound 1 was prepared as described in Example 538.

Title Compound : N- [4-Benzyl-1- (4-fluoro-benzylsulfamoyl)-piperidin-4- ylmethyl] -2-methoxy-benzamide was prepared using methodology described in Example 17. NMR 1H (CDC13) 8 (ppm) 1.50-1-70 (4 H, m), 2.66 (2 H, s), 3.20-3. 50 (6 H, m), 4.02 (3 H, s), 4.19 (2 H, d, J=5.0 Hz), 4.58 (1 H, bs), 6.99-7. 33 (10 H, m), 7.48 (1 H, td, J= 1.7, 8.0 Hz), 8.08 (1 H, bt, J= 5.7 Hz), 8.20 (1 H, dd, J= 1.8, 7.8 Hz).

EXAMPLE 542 Example 542 was prepared using methodology described in Example 541. Example Structure Name (M+ 1) + 542 o o'CH, N- [4-Benzyl-l- (2-methoxy- 476. 2 vNJA ethylsulfamoyl)-piperidin-4-ylmethyl]- v 4, NJ v 2-methoxy-benzamide Oto N~ CH3

EXAMPLE 543

N- (4-Benzyl-1-dimethylsulfamoyl-piperidin-4-ylmethyl)-2-methox y-benzamide Synthesis

Compound 1: Compound 1 was prepared as described in Example 538.

Title Compound : N- (4-Benzyl-1-dimethylsulfamoyl-piperidin-4-ylmethyl)- 2-methoxy-benzamide was prepared using methodology described in Example 16.

LRMS in/z 446 (M+H) +.

EXAMPLES 544 AND 545

4- [2- (4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine- 1-carboxylic acid tert-butyl ester and <BR> 4- [l- (4-Chloro-benzyl)-lH-tetrazol-5-yl]-4-phenyl-piperidine- 1-carboxylic acid tert-butyl ester Synthesis NON oN NaN3, NH4CI N NH 4_Chlorobenzyl bromid N DMSO, 145°C N K2C03, CH3CN I _ NN-\"N 1 2 N=N/N-N wN, N I NN N N CI-N /CI 0A0S 0A0S Compound 1: Compound 1 was prepared using methodology described in Example 74. LRMS 287 (M+H) +.

Compound 2: Compound 1 (286 mg, 1.0 mmol), sodium azide (325 mg, 5.0 mmol) and ammonium chloride (268 mg, 5.0 mmol) in DMF (1.5 mL) was heated at 145 °C for 24 hours. After cooling to room temperature the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by

silica gel chromotography using CHCl3/MeOH (95: 5) as eluent to give a white solid compound 2,250 mg (76% yield). NMR 1H (CDC13) 8 (ppm) 1.42 (9 H, s), 2.05-2. 20 (2 H, m), 2.60-3. 30 (4 H, m), 3.90 (2 H, bd, J=13. 6 Hz), 7.15-7. 30 (5 H, m).

Title Compounds: Compound 2 (240 mg, 0.73 mmol), K2CO3 (111 mg, 0.8 mmol), 4-chlorobenzyl bromide (164 mg, 0.8 mmol) in acetonitrile (6 mL) was heated at 70 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water, saturated sodium chloride, dried over anhydrous sodium chloride, filtered and concentrated. The residue was purified by silica gel chromotography using Hexanes/Ethyl acetate (3: 1) as eluent to give a white solid 4- [2- (4-chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine-l-ca rboxylic acid tert-butyl ester, 244 mg (74% yield) NMR IH (CDC13) 8 (ppm) 1.44 (9 H, s), 2.10- 2.25 (2 H, m), 2.75-2. 90 (4 H, m), 3.95 (2 H, bs), 5.68 (2 H, s), 7.16-7. 35 (9 H, m).

LCMS Rt 1.38 min, [M+1] 454.0 and white solid 4- [I- (4-chloro-benzyl)-lH-tetrazol- 5-yl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, 38 mg (11% yield) NMR 'H (CDC13) 8 (ppm) 1.43 (9 H, s), 2.00-2. 55 (4 H, m), 2.75-2. 90 (2 H, m), 3.00 (1 H, bs), 3.35 (1 H, bs), 3.82 (2 H, bs), 5.92 (2 H, bs), 6.71 (2 H, d, J= 8.6 Hz), 7.09 (2 H, d, J= 1.4 Hz), 7.11 (1 H, d, J= 1.9 Hz), 7.22-7. 38 (4 H, m). LCMS Rt 1.38 min, [M+1] 454.2 EXAMPLE 546 4- [2- (4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine- 1-carboxylic acid ethyl ester Synthesis

2<BR> 1 Compound 1: Compound 1 was prepared as described in Example 544.

Compound 2: Compound 1 (236 mg, 0.52 mmol) in dichloromethane (3 mL) and TFA (1 mL) was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in ethyl acetate (20 mL), washed with 1N NaOH (2 x 5 mL), water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated to give an oil compound 2,181 mg (98%). NMR H (CDC13) 8 (ppm) 1.24 (3 H, t, J=7.0 Hz), 2.11 (2 H, bs), 2.43 (2 H, bs), 3.05 (1 H, bs), 3.35 (1 H, bs), 3.85-3. 95 (2 H, bs), 4.11 (2 H, q, J=7.0 Hz), 4.91 (2 H, s), 6.72 (2 H, d, J=8.4 Hz), 7.21 (2 H, d, J=8.4 Hz), 7.10 (2 H, d, J=6.1 Hz), 7.29-7. 38 (3 H, m). [M+1] 426.0 Title Compound : 4- [2- (4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl- piperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. LRMS m/z 455 (M+H) +.

EXAMPLE 547 {4- [2- (4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidin-1-yl} - phenyl-methanone Synthesis

Compound 1: Compound 1 was prepared as described in Example 544.

Title Compound : {4- [2- (4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl- piperidin-l-yl}-phenyl-methanone was prepared using methodology described in Example 94. LRMS 7tiz 459 (M+H) +.

EXAMPLE 548

4- [2- (4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl-piperidine- 1-carboxylic acid phenylamide Synthesis

Compound 1: Compound 1 was prepared as described in Example 544.

Title Compound : 4- [2- (4-Chloro-benzyl)-2H-tetrazol-5-yl]-4-phenyl- piperidine-l-carboxylic acid phenylamide was prepared using methodology as described in Example 390. LRMS m/z 474 (M+H) +.

EXAMPLES 549 TO 598 Examples 549 to 598 were prepared using methodology described in Example 546, Example 547 and Example 548. Example Structure Name (M+1) + 549/Nb 4- (2-Benzyl-2H-tetrazol-5-yl)-4- 392. 2 phenyl-piperidine-1-carboxylic acid ethyl ester N O O<CH3 550 r N 4-Phenyl-4- [2- (3-triauoromethoxy- 476. 2 benzyl)-2H-tetrazol-5-yl]- piperidine-1-carboxylic acid ethyl ester OO'CH3 551 X t-NN 4-[2-(3-Methyl-benzyl)-2H-tetrazol-406. 2 5-yl]-4-phenyl-piperidine-1- CH3 N carboxylic acid ethyl ester O ; O^CH3 552 ( N 4- [2- (3-Bromo-bcnzyl)-2H-tetrazol- 470. 1 5-yl]-4-phenyl-piperidine-1- N carboxylic acid ethyl ester oRO^CH3 553 O-CH3 4-12- [2- (3-Methoxy-phenyl)-2-oxo- 450. 2 A Wd ethyl]-2H-tetrazol-5-yl}-4-phenyl- piperidine-l-carboxylic acid ethyl ester 554 4- [2- (3, 4-Dichloro-benzyl)-2H- 460. 1 tetrazol-5-yl]-4-phenyl-piperidine-1- LJ'C carboxylic acid ethyl ester O O^CH3 Example Structure Name (M+1) + 555 4- [2- (4-Fluoro-3-trifluoromethyl- 478. 2 benzyl)-2H-tetrazol-5-yl]-4-phenyl- N F piperidine-l-carboxylic acid ethyl 0-7-0-CH3 ester 556-NN 4- [2- (4-Methyl-benzyl)-2H-tetrazol- 406. 2 -N 5-yll-4-phenyl-piperidine-l- N H3 carboxylic acid ethyl ester O ; O4CH3 557 \/N, 4- [2- (2-Oxo-2-phenyl-ethyl)-2H- 420. 2 tetrazol-5-yl]-4-phenyl-piperidine-1- EN carboxylic acid ethyl ester O O^CH3 558-N 4- [2- (4-tert-Butyl-benzyl)-2H- 448. 2 tetrazol-5-yl]-4-phenyl-piperidine-l- carboxylic acid ethyl ester OXO^CH3 559 4-Phenyl-4- [2- (4-trifluoromethoxy- 476. 2 benzyl)-2H-tetrazol-5-yl]- OCF3 piperidine-1-carboxylic acid ethyl O O^CH3 ester 560 d NN 4-(2-Naphthalen-2-ylmethyl-2H-442. 2 tetrazol-5-yl)-4-phenyl-piperidine-1- Nu carboxylic acid ethyl ester OXO^CH3 561 4- [2- (3-Fluoro-4-trifluoromethyl- 478. 2 CN F benzyl)-2H-tetrazol-5-yl]-4-phenyl- N F3 piperidine-l-carboxylic acid ethyl OO-CHg ester 562/NNN 4-[2-(4-Bromo-benzyl)-2H-tetrazol-470. 1 5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester O ; O^CH3 563 4- [2- (3, 5-Difluoro-benzyl)-2H- 428. 2 NN V tetrazoI-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester OXO^CH3 Example Structure Name (M+1) + 564 ci 4- [2- (2, 4-Dichloro-benzyl)-2H- 460. 1 tetrazol-5-yl]-4-phenyl-piperidine-1- tNJ wCI carboxylic acid ethyl ester OXO4CH3 565/ Nt C ! 4- [2- (2-Chloro-benzyl)-2H-tetrazol- 426. 1 5-yll-4-phenyl-piperidine-l- N carboxylic acid ethyl ester o ; O^CH3 566 4- [2- (3-Chloro-benzyl)-2H-tetrazol- 426. 1 <N vCI 5-yl]-4-phenyl-piperidine-1- N carboxylic acid ethyl ester OXC (--CH3 . O2O^CH3 567 n NNN 4-[2-(4-Chloro-benzyl)-2H-tetrazol-426. 1 5-yl]-4-phenyl-piperidine-1- NJ CI carboxylic acid ethyl ester O1O^CH3 568 n N NN 4-[2-(2-Oxo-propyl)-2H-tetrazol-5-358. 2 N'3 yl]-4-phenyl-piperidine-l- 0 N carboxylic acid ethyl ester OXO^CH3 569 4- (2-Allyl-2H-tetrazol-5-yl)-4- 342. 2 phenyl-piperidine-l-carboxylic acid ethyl ester O ; O^CH3 570-. NN 4- [2- (3-Methoxy-benzyl)-2H- 422. 2 N tetrazol-5-yl]-4-phenyl-piperidine-l- N CH3 carboxylic acid ethyl ester o ; O^CH3 571 n N-ch 4-[2-(4-Methoxy-benzyl)-2H-422. 2 N tetrazol-5-yl]-4-phenyl-piperidine-l- N Jazz carboxylic acid ethyl ester NO j j OOCH3CH3 572 lS NNN O-CH3 4-[2-(2-Methoxy-benzyl)-2H-422. 2 tetrazol-5-yl]-4-phenyl-piperidine-l- N carboxylic acid ethyl ester O ; O^CH3 Example Structure Name (M+1) + 573 H3CO 4- [2- (3, 5-Dimethoxy-benzyl)-2H- 452. 2 33OCH3 tetrazol-5-yl]-4-phenyl-piperidine-1- carboxylic acid ethyl ester N O O^CH3 574 n N-N 4-[2-(2-Methyl-benzyl)-2H-tetrazol-406. 2 0--N X 5-yl]-4-phenyl-piperidine-1- N carboxylic acid ethyl ester O O^CH3 575 0-<FF 4-Phenyl-4- [2- (2-trifluoromethoxy- 476. 1 F benzyl)-2H-tetrazol-5-yl]- N-d piperidine-l-carboxylic acid ethyl O ; O^CH3 ester 576 4- [2- (4-Chloro-benzyl)-2H-tetrazol- 454. 2 5-yl]-4-phenyl-piperidine-1- carboxylic acid tert-butyl ester N CH3 COtCHs CH3 577 N-) F 4- [2- (2-Fluoro-benzyl)-2H-tetrazol- 410. 2 19 X 5-yl]-4-phenyl-piperidine-1- N carboxylic acid ethyl ester O-OCHs 578 4- [2- (3-Fluoro-benzyl)-2H-tetrazol- 410. 2 <-N wF 5-yl]-4-phenyl-piperidine-1- N carboxylic acid ethyl ester OXO^CH3 579 4- [2- (4-Fluoro-benzyl)-2H-tetrazol- 410. 2 5-yl]-4-phenyl-piperidine-l- carboxylic acid ethyl ester OXO^CH3 580-N F 4-Phenyl-4- [2- (2-trifluoromethyl- 460. 2 benzyl)-2H-tetrazol-5-ylj- piperidine-l-carboxylic acid ethyl ester OXO-CH3 581 FF 4-Phenyl-4- [2- (3-trifluoromethyl- 460. 2 benzyl)-2H-tetrazol-5-yl]- N piperidine-1-carboxylic acid ethyl ester Example Structure Name (M+1) + 582/N N, 4-Phenyl-4-[2-(4-trifluoromethyl-460. 2 benzyl)-2H-tetrazol-5-yl]- F piperidine-l-carboxylic acid ethyl OXO-CH3 F F ester 583 Cl {4-[2-(4-Chloro-benzyl)-2H-476. 1 tetrazol-5-yl]-4-phenyl-piperidin-1- C yl}-(4-fluoro-phenyl)-methanone NN N 'F 584 Cl {4- [2- (4-Chloro-benzyl)-2H- 472. 2 tetrazol-5-yl]-4-phenyl-piperidin-1- yl I-p-tolyi-methanone NU p N3 3 585 Cl 1- {4- [2- (4-Chloro-benzyl)-2H- 472. 2 t tetrazol-5-yl]-4-phenyl-piperidin-1- N yl}-2-phenyl-ethanone nu I 586 Cl 1-{4-[2-(4-Chloro-benzyl)-2H-490. 2 tetrazol-5-yl]-4-phenyl-piperidin-l- yl}-2- (4-fluoro-phenyl)-ethanone NJ F N 0< 587 Cl 1- {4- [2- (4-Chloro-benzyl)-2H- 486. 2 tetrazol-5-yl]-4-phenyl-piperidin-l- (Xi J yl}-2-p-tolyl-ethanone I tNj SCH3 0H 0 588 ci 1- {4- [2- (4-Chloro-benzyl)-2H- 486. 2 tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-3-phenyl-propan-1-one 0 0 Example Structure Name (M+1) + 589 Cl 1- {4-[2-(4-Chloro-benzyl)-2H-504. 2 tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-3- (4-fluoro-phenyl)-propan-1- one ONZE N F 590 C 1- {4- [2- (4-Chloro-benzyl)-2H- 500. 2 tetrazol-5-yl]-4-phenyl-piperidin-l- yl}-3-p-tolyl-propan-1-one N N ICH 3 591 Cl 1- {4-[2-(4-Chloro-benzyl)-2H-488. 1 tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-2-phenoxy-ethanone N N C.-O I 592 Cl 4- [2- (4-Chloro-benzyl)-2H-tetrazol- 488. 1 5-yl]-4-phenyl-piperidine-1- carboxylic acid benzyl ester N kN N 0 593 Cl 1- {4- [2- (4-Chloro-benzyl)-2H- 426. 2 tetrazol-5-yll-4-phenyl-piperidin-l- N-NN-0 yl}-2-methoxy-ethanone N , N O>O-CH3 594 P'4- [2- (4-Chloro-benzyl)-2H-tetrazol- 491. 2 5-yl]-4-phenyl-piperidine-1- carboxylic acid (4-fluoro-phenyl)- amide amide N, SF OXN Example Structure Name (M+1) + 595 Cl 4- [2-(4-Chloro-benzyl)-2H-tetrazol-489. 1 t 5-yl]-4-phenyl-piperidine-1- carbothioic acid phenylamide 596 ci 14- [2- (4-Chloro-benzyl)-2H- 459. 2 M tetrazol-5-yl]-4-phenyl-piperidin-1- N-N-0 yl}-pyridin-4-yl-methanone N y N N 597 Cl {4- [2- (4-Chloro-benzyl)-2H- 459. 2 tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-pyridin-2-yl-methanone N "N 0 1- {4- [2- (4-Chloro-benzyl)-2H- 478. 1 tetrazol-5-yl]-4-phenyl-piperidin-1- yl}-2-thiophen-2-yl-ethanone N, J S1 O 0 EXAMPLE 599

4- [1-(4-Chloro-benzyl)-1H-tetrazol-5-yl]-4-phenyl-piperidine- 1-carboxylic acid ethyl ester Synthesis

2<BR> 1 Compound 1: Compound 1 was prepared as described in Example 545.

Compound 2: Compound 1 (31 mg, 0.068 mmol) in dichloromethane (0.75 mL) and TFA (0.25 mL) was stirred at room temperature for 1.5 hour then concentrated. The residue was dissolved in ethyl acetate (10 mL), washed with IN NaOH (2 x 5 mL), water, saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give an oil compound 6,20 mg (83%). NMR H (CDC13) 8 (ppm) 1.72 (1 H, bs), 2.12-2. 21 (2 H, m), 2.46 (2 H, bd, J= 13.7 Hz), 2.94 (4 H, bs), 4.92 (2 H, s), 6.71 (2 H, d, J=8. 4 Hz), 7.12 (2 H, d, J= 6. 4 Hz), 7.16 (2 H, d, J= 11.3 Hz), 7.21-7. 36 (3 H, m).

Title Compound: 4- [l- (4-Chloro-benzyl)-lH-tetrazol-5-yl]-4-phenyl- piperidine-1-carboxylic acid ethyl ester was prepared using methodology described in Example 2. NMR H (CDC13) 8 (ppm) 1.24 (3 H, t, J=7.0 Hz), 2.11 (2 H, bs), 2.43 (2 H, bs), 3.05 (1 H, bs), 3.35 (1 H, bs), 3.85-3. 95 (2 H, bs), 4.11 (2 H, q, J=7.0 Hz), 4.91 (2 H, s), 6.72 (2 H, d, J=8.4 Hz), 7.21 (2 H, d, J=8.4 Hz), 7.10 (2 H, d, J=6.1 Hz), 7.29-7. 38 (3 H, m). [M+1] 426.0 EXAMPLE 600 1- {4- [1- (4-Chloro-benzyl)-1 H-tetrazol-5-yl]-4-phenyl-piperidin-1-yl}-<BR> <BR> 3-phenyl-propan-1-one Synthesis

Compound 1: Compound 1 was prepared as described in Example 599.

Title Compound : 1- {4- [1- (4-Chloro-benzyl)-1 H-tetrazol-5-yl]-4-phenyl- piperidin-l-yl}-3-phenyl-propan-1-one was prepared using methodology described in Example 390. NMR H (CDC13) 8 (ppm) 1.72-1. 77 (1 H, m), 2.09-2. 27 (2 H, m), 2.48-2. 62 (3 H, m), 2.69-2. 77 (1 H, m), 2.92-2. 96 (2 H, m), 3.63 (2 H, dd, J= 3.0, 8.0 Hz), 4.31-4. 35 (1 H, m), 4.81 (1 H, d, J=15.8 Hz), 4.98 (1 H, d, J=15.8 Hz), 6.71 (2 H, d, J=8.5 Hz), 6.71 (2 H, d, J=8.5 Hz), 7.06-7. 38 (8 H, m). [M+1] 486.3 EXAMPLE 601 1- [4- (5-Phenethyl- [1, 2,4] oxadiazol-3-yl)-4-phenyl-piperidin-1-yl]- 3-phenyl-propan-1-one Synthesis Nu2 l XN NH20H. HCI, MeONa N OH PhCH2CH2COCI L. J F ;" L J EtsN. THF" N ! N", 2 1 2 y 2 /NH2//N-O NO 1 N \ I O (n-Bu) 4NF N THF N 0A0S 0A0S 3 4 3 4 o /I N O CI _4N HCI N \ Dioxane N NEt3 H THF 5 /I N-O N 5 O v Y 09

Compound 1: Compound 1 was prepared as described in Example 74.

Compound 2: To hydroxylamine hydrochloride (4.25 g, 61.2 mmol) and sodium methoxide (3.30 g, 61.2 mmol) in PrOH (100 mL) was added compound 1 (5.8 g, 20.4 mmol). The reaction mixture was heated at reflux overnight, diluted with Ethyl acetate (200 mL), washed with water, sat. sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a white solid compound 2,4. 60 g (72% yield). LCMS Rt 1.06 min, [M+1] 320.2.

Compound 3: Compound 2 (31 mg, 0.10 mmol), Et3N (15 mg, 0. 15 mmol) and hydrocinnamoyl chloride (19 mg, 0.11 mmol) in tetrahydrofuran (0.5 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid compound 3,0. 03 g (66% yield).

Compound 4 : To compound 3 (30 mg, 0. 066 mmol) in dry tetrahydrofuran (0. 5mL) was added 0.13 mL (0.132 mmol) of tetrabutyl ammonium fluoride. After stirring for two hours at room temperature the reaction mixture was diluted with Ethyl acetate (5 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid compound 4 sufficiently pure to be taken on to the next step.

Compound 5: Compound 5 were prepared using methodology described in Example 85 using hydrochloric acid instead of trifluoroacetic acid to accomplish nitrogen deprotection. LRMS m/z 334 (M+H) +.

Title Compound : 1- [4- (5-Phenethyl- [1, 2,4] oxadiazol-3-yl) -4-phenyl- piperidin-l-yl]-3-phenyl-propan-1-one was prepared using methodology described in Example 94. LRMS 11z/Z 466 (M+H) +.

EXAMPLES 602 TO 626 Examples 602 to 626 were prepared as described in Example 601. Example Structure Name (M+H) + 602 N r-/\ l- {4- [5- (2-Methoxy-phenyl)- 468. 2 N [1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidm-1-yl}-3-phenyl-propan- N . 1-one 'w v i 603 NC'1- [4- (5-Phenethyl- 452. 2 [1, 2, 4] oxadiazol-3-yl)-4-phenyl- piperidin-1-yl]-2-phenyl- NJ ethanone Wo Example Stiucture Name (M+H) + 604 \ N _ 2- (4-Fluoro-phenyl)-1- [4- (5- 470. 2 N phenethyl- [1, 2, 4] oxadiazol-3-yl)- F L J 4-phenyl-piperidin-l-yl]- ethanone 0 605 N0 1- [4- (5-Phenethyl- 466. 2 vN < [1, 2, 4] oxadiazol-3-yl)-4-phenyl- H, /NJ piperidin-1-yl]-2-p-tolyl- ethanone 0 606fi T'\ 3- (4-Fluoro-phenyl)-l- [4- (5-484. 2 N phenethyl- [1, 2, 4] oxadiazol-3-yl)- NU 4-phenyl-piperidin-1-yl]-propan- 1-one FJv 607r r l- [4- (5Phenethyl-480. 3 [1, 2, 4] oxadiazol-3-yl)-4-phenyl- kN piperidin-1-yl]-3-p-tolyl-propan- ~ 0 l-one H3CX 608 NI-1-14- [5- (4-Chloro-benzyl)- 472. 2 N [1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidin-l-yl}-2-phenyl- Xo ethanone o 609 1-14- [5- (4-Chloro-benzyl)- 490. 2 vN ß [1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidin-l-yl}-2- (4-fluoro- N phenyl)-ethanone 9 o, 610 NI I-f 4- [5- (4-Chloro-benzyl)- 486. 2 N [1, 2, 4] oxadiazol-3-yl]-4-phenyl- H3c piperidin-1-yl}-2-p-tolyl- i NJ ethanone . 611 1-14- [5- (4-Chloro-benzyl)- 486. 2 zon [1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3-phenyl-propan- N \CI I-one 1-one w o i Example Structure Name (M+H) + 612 N0 I-f4- [5- (4-Chloro-benzyl)- 504. 2 N [1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3- (4-fluoro- tf »'phenyl)-propan-l-one F F 613 1-14- [5- (4-Chloro-benzyl)- 500. 2 N [1, 2, 4] oxadiazol-3-yl]-4-phenyl- kY \=S lpiperidin-l-yl}-3-p-tolyl-propan- zozo I \ 0 2-one HSCJW 614 NI 1-14- [5- (4-Chloro-benzyl)- 488. 2 N [1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-2-phenoxy- ethanone ^ o 615/N-° [4- (5-Benzyl- [1, 2, 4] oxadiazol-3- 442. 2 N yl)-4-phenyl-piperidin-1-yl]- (4- fluoro-phenyl)-methanone Ho O Fw 616 \ y 1- [4- (5-Benzyl- [1, 2, 4] oxadiazol- 438. 2 3-yl)-4-phenyl-piperidin-1-yl]-2- phenyl-ethanone N Xo 617 NI 1- [4- (S-Benzyl- [1, 2, 4] oxadiazol- 456. 2 N 3-yl)-4-phenyl-piperidin-1-yl]-2- (4-fluoro-phenyl)-ethanone N 0 618 NI 1- [4- (5-Benzyl- [1, 2, 4] oxadiazol- 452. 2 N 3-yl)-4-phenyl-piperidin-1-yl]-2- H3C N p-tolyl-ethanone 0 619 b 1- [4- (5-Benzyl- [1, 2, 4] oxadiazol- 452. 2 N 3-yl)-4-phenyl-piperidin-1-yl]-3- phenyl-propan-l-one N W.. Example Structure Name (M+H) + N 0 620 iqI-1- [4- (5-Benzyl- [1, 2, 4] oxadiazol- 470. 2 N 3-yl)-4-phenyl-piperidin-1-yl]-3- (4-fluoro-phenyl)-propan-1-one N F F 621 1- [4- (5-Benzyl- [1, 2, 4] oxadiazol- 466. 2 3-yl)-4-phenyl-piperidin-1-yl]-3- p-tolyl-propan-1-one N hic nec 622 N-°\ l- [4- (5-Phenethyl- 458. 2 N [1, 2, 4] oxadiazol-3-yl)-4-phenyl- piperidin-1-yl]-2-thiophen-2-yl- N ethanone o ls 623 N-o 4- (5- (4-Chloro-benzyl)- 488. 2 vN < t 1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidine-l-carboxylic acid benzyl ester oo I w 624 Nli 1- [4- (5-Benzyl- [1, 2, 4] oxadiazol- 444. 2 3-yl)-4-phenyl-piperidin-1-yl]-2- thiophen-2-yl-ethanone N 0 625 N11 N-o 1- {4- [5- (4-Methoxy-benzyl)- 482. 2 N [1, 2, 4] oxadiazol-3-yl]-4-phenyl- piperidin-1-yl}-3-phenyl-propan- N CH3 1-one o I v 626 N 3- (4-Fluoro-phenyl)-l-14- [5- (4- 500. 2 methoxy-benzyl)- _ [1, 2, 4] oxadiazol-3-yl]-4-phenyl- N \OCHa piperidin-l-yl}-propan-l-one oH F EXAMPLE 627

4- (5-Fluoro-l-methyl-lH-benzoimidazol-2-yl)-4-phenyl-piperidin e- 1-carboxylic acid benzyl ester Synthesis

Compound 1: Compound 1 is commercially available.

Compound 2: 2,5-Difluoronitrobenzene (1. 0 g, 6.29 mmol), methylamine hydrochloride (2.12 g, 31.43 mmol) and potassium carbonate (4.34 g, 31.43 mmol) in DMSO (10 mL) was stirred for 24 hours, diluted with Et20 (200 mL), washed with water (3 times), brine, dried over anhydrous sodium sulfate and concentrated to give compound 2 as an orange solid 1. 1 g (100 %).

Compound 3: Compound 2 (1.1 g, 6.29 mmol) and 10% Pd on charcoal (300 mg) in methanol (20 mL) was stirred under hydrogen for 24 hours, filtered over celite and concentrated. The residue was purified by silica gel chromotography using Hexanes/Ethyl acetate (2: 1) as eluent to give a white solid compound 3,672 mg (74% yield). NMR 1H (CDC13) 8 (ppm) 2.83 (3 H, s), 3.28 (3 H, bs), 6.40-6. 60 (3 H, m).

Compound 4: Compound 4 was prepared as described in Example 323.

Compounds 5 and 6: Compound 4 (700 mg, 2.06 mmol) in thionyl chloride was heated at reflux for 2 hours then concentrated. The residue was dissolved in CH2C12 (3.5 mL) and cooled to 0 °C. Compound 3 (289 mg, 2.06 mmol) in CH2Cl2 (3. 5 mL) followed by Et3N (1.44 mL, 10.3 mmol) were added. After 1 hour the reaction mixture was diluted with Ethyl acetate (30 mL), washed with IN NaOH, water, brine, dried over anh. sodium sulfate and concentrated. The residue was purified by silica gel chromotography using Hexanes/Ethyl acetate (2: 1) as eluent to give a white solid compound 5 and compound 6 521 mg (55% yield) as an inseparable mixture. LCMS Rt 1.42 min and 1.52, [M+1] 462.2.

Title Compound: The mixture of compound 5 and compound 6 (521 mg, 1.12 mmol) in glacial acetic acid (5 mL) was heated at reflux for 2 hours then concentrated. The residue was purified by silica gel chromotography using Hexanes/Ethyl acetate (2: 1) as eluent to give a white solid 4- (5-fluoro-1-methyl-1H- benzoimidazol-2-yl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester, 365 mg (73% yield). NMR 1H (CDC13) 6 (ppm) 2.05-2. 40 (2 H, m), 2.55-2. 75 (2 H, m), 3.22 (3 H, s), 3.25-3. 40 (1 H, m), 3.50-3. 70 (1 H, m), 5.14 (2 H, s), 7.01 (1 H, dt, J= 2. 4, 9.1 Hz), 7.09-7. 35 (13 H, m), 7.48 (1 H, dd, J= 2.2, 9.4 Hz).

LCMS Rt 1.41 min, [M+1] 442.2.

EXAMPLES 628 TO 646 Examples 628 to 646 were prepared as described in Example 627. Example Structure Name (M+1) + 628 4- (lH-Benzoimidazol-2-ylmethyl)- 426. 2 4-phenyl-piperidine-l-carboxylic acid benzyl ester N 00, 629 cHs 4-(1-Methyl-lH-benzoimidazol-2-440. 2 N ylmethyl)-4-phenyl-piperidine-l- N carboxylic acid benzyl ester N N oo \ 630 4-(lH-Benzoimidazol-2-yl)-4-412. 2 N phenyl-piperidine-l-carboxylic acid benzyl ester N CJ'O I 631 c F 1- [4- (5-Fluoro-l-metbyl-IH- 442. 2 benzoimidazol-2-yl)-4-phenyl- r"-i piperidin-1-yl]-3-phenyl-propan-1- N one o, \ 632 CH 1- [4- (5-Fluoro-l-methyl-IH- 444. 2 benzoimidazol-2-yl)-4-phenyl- piperidin-1-yl]-2-phenoxy-ethanone N J / 633/ HN F 5-Fluoro-2- [1- (4-fluoro- 468. 2 benzenesulfonyl)-4-phenyl- piperidin-4-yl]-1-methyl-1H- N benzoimidazole os o3, sg /F Example Structure Name (M+1) + 634/°" 485. 2 N N N N N''N I \ F 635/°"NF 1- [4- (5-Fluoro-1-methyl-1H- 462. 2 N benzoimidazol-2-yl)-4-phenyl- piperidin-1-yl]-2- (4-fluoro- N phenoxy)-ethanone oxo F 636 N F 1- [4- (5-Fluoro-lH-benzoimidazol-2- 458. 2 N yl)-4-phenyl-piperidin-1-yl]-3- (4- methoxy-phenyl)-propan-1-one 1 N p \ /OiCNa 637 N F 1- [4- (5-Fluoro-lH-benzoimidazol-2- 442. 2 yl)-4-phenyl-piperidin-1-yl]-4- phenyl-butan-l-one nez o ; 43 638 N F 1- [4- (5-Fluoro-lH-benzoimidazol-2- 482. 2 N yl)-4-phenyl-piperidin-1-yl]-2- (3- trifluoromethyl-phenyl)-ethanone N F ° \ F F F 639 N ci 5-Chloro-2- [I- (3-fluoro- 470. 1 benzenesulfonyl)-4-phenyl- -N tND piperidin-4-yl]-1 H-benzoimidazole N oS C F _F 640 N ci 5-Chloro-2- [I- (4-fluoro- 470. 1 N benzenesulfonyl)-4-phenyl- X piperidin-4-yl]-1 H-benzoimidazole oS N 0, 1 r F Example Structure Name (M+1) + 641 C"3 467. 2 'N N N N 642 F 495. 2 1 N zu N CL 643 F 481. 2 'N- N N N) I-l 644 N 1- [4- (l-Methyl-lH-benzoimidazol- 438. 3 2-ylmethyl)-4-phenyl-piperidin-l- yl-3-phenyl-propan-1-one N 0 O 645/r 2- [l- (4-Methoxy-benzenesulfonyl)- 476. 2 \ 4-phenyl-piperidin-4-ylmethyl]-1- methyl-lH-benzoimidazole N I O=S=0 chia . O O=S=o 646 '"4- (5-Chloro-lH-benzoimidazol-2- 384. 1 N yl)-4-phenyl-piperidine-l-carboxylic acid ethyl ester ob HIC- EXAMPLE 647

4-tert-Butoxycarbonylamino-4-phenyl-piperidine-1-carboxylic acid benzyl ester Synthesis 0 Ph Ph0'OPh3 \ N3 tBuOH OPE NEt3 l chlorobenzene OO I THF O O 1 2 2 I H NJ + NJ OO I w OO L

3 Compound 1: Compound 1 was prepared as described in Example 323.

Compound 2: A solution of compound 1 (0.62 g; 1.8 mmol) in tetrahydrofuran (40 mL) was cooled to 0°C and treated with triethylamine (0.38 mL; 2.7 mmol) and diphenylphosphoryl azide (0.44 mL; 2.0 mmol). The cooling bath was removed and the reaction mixture was allowed to stir at room temperature 18 h. The tetrahydrofuran was removed by evaporation and the crude residue was purified by column chromatography on silica gel using 8: 2 hexane: ethyl acetate as the eluent to give 0.67g of compound 2. LRMS m/z 365 (M+H) +.

Title Compound: A solution of compound 2 (0.67 g; 1.8 mmol) in chlorobenzene (15 mL) was treated with t-butanol (25 mL) and heated at 115°C for 20

h. The chlorobenzene was removed by evaporation and the residue was subjected to column chromatography on silica gel using an 8: 2 hexane: ethyl acetate to 1 : 1 hexane: ethyl acetate gradient as the eluent to give 0.05 g of 4-tert- butoxycarbonylamino-4-phenyl-piperidine-1-carboxylic acid benzyl ester as a colorless oil LRMS 7X/Z 411 (M+H) +and 0.2 g compound 3 as a colorless oil LRMS m/z 337 (M+H) +.

EXAMPLE 648 4-(2-Methoxy-benzoylamino)-4-phenyl-piperidine-1-carboxylic acid benzyl ester Synthesis Compound 1: Compound 1 was prepared as described in Example 626.

Compound 2: A solution of compound 1 (0. 05g ; 0.1 mmol) in dichloromethane (2 mL) was treated with trifluoroaceric acid (1 mL) and allowed to stir at room temperature for 1 h at which time LCMS indicated complete consumption of compound 1. Additional dichloromethane (20 mL) and 1 N sodium hydroxide (20 mL) were added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to give

0.03 g of compound 2 that was used in the next step without additional purification.

LCMS nalz = 311 (M+H) + Title Compound: A solution of compound 2 (0.03g ; 0.009 mmol) in tetrahydrofuran (2 mL) was treated with triethylamine (0.1 mL; 0.7 mmol) and o- anisoyl chloride (0.05 g; 0.3 mmol) at room temperature. After stirring 15 h the tetrahydrofuran was removed by evaporation and the residue was purified by prep LC to give 0.011 g of compound 4-(2-methoxy-benzoylamino)-4-phenyl-piperidine-1- carboxylic acid benzyl ester as a white solid. LCMS m/z = 461 (M+H) + EXAMPLE 649 4- [3- (2-Methoxy-benzyl)-ureido]-4-phenyl-piperidine-l-carboxylic acid benzyl ester Synthesis Compound 1: Compound 1 was prepared as described in Example 626.

Title Compound : A solution of compound 1 (0.05g ; 0.15 m mol) in anyhydrous tetrahydrofuran (2 mL) was treated with 2-methoxybenzyl amine (0. 041 g ; 0.30 mmol) at room temperature. After stirring 2 h the tetrahydrofuran was removed by evaporation and the residue was purified by prep LC to give 0.015 g of 4- [3- (2-

methoxy-benzyl)-ureido]-4-phenyl-piperidine-1-carboxylic acid benzyl ester as a white solid. LCMS m/z = 475 (M+H) +.

EXAMPLES 650 TO 652 Examples 650 to 652 were prepared as described in Example 649. Example Structure Name M+H 650 H H CH3 4- [3- (2-Methoxy-phenyl)-ureido]-4- 461 N N phenyl-piperidine-l-carboxylic acid benzyl ester I N 651 e 4-(3-Phenethyl-ureido)-4-phenyl-459 '0 ° piperidine-l-carboxylic acid benzyl N N ester (j 0 1 N oAon3 652 n H H n 4-(3-Isoquinolin-1-yl-ureido)-4-482 Ny N phenyl-piperidine-carboxylic acid 0 N benzyl ester N oIT' EXAMPLE 653

3-Amino-pyrazine-2-carboxylic acid (4-phenyl-piperidin-4-ylmethyl)-amide Synthesis

Compound 1: Compound 1 is commercially available.

Compound 2: A solution of compound 1 (20 g; 90 mmol) in 1 N sodium hydroxide (200 mL) and tetrahydrofuran (50 mL) was treated with di-tert-butyl dicarbonate (19.7 g; 90.3 mmol) at room temperature. After stirring 24 h the reaction mixture was adjusted to pH = 7 by the addition of 1 N hydrochloric acid and washed with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated.

The crude product was recyrstallized from the minimum amount of ethanol to give 20 g compound 2 as a white solid. LRMS n/z = 287 (M+H) + Compound 3: A solution of compound 2 (4.5 g; 15.7 mmol) in ethanol (42.5 mL) and acetic acid (7.5 mL) was treated with platinum oxide (250 mg) and hydrogenated at 60 psi for 12h. Analysis by thin layer chromatography indicated the reaction was not complete. Additional platinum oxide (124 mg) was added and the reaction mixture hydrogenated at 60 psi for another 12 h. The reaction mixture was filtered through celite and concentrated to give 4.6 g of compound 3 as a colorless oil that was used without additional purification. LRMS m/z = 291 (M+H) + Compound 4: A suspension of 3-amino-pyrazine-2-carboxylic acid (2.9 g; 20.8 mmol) in tetrahydrofuran (30 mL) was treated with triethylamine (7 mL; 50 mmol) followed by benzotriazole-1-yl-oxy-tris- (dimethylamino)- phosphoniumhexafluorophosphate (8.8 g; 19.9 mmol) at room temperature. After 15

minutes of stirring the reaction mixture became homogeneous and compound 3 (4.6 g; 15.8 mmol) was added as a solution in tetrahydrofuran (20 mL). The reaction was heated at 60°C for 12 h. The solvent was removed by rotary evaporation and the crude product was purified directly by column chromatography on silica gel using 1: 1 ethyl acetate: hexane as the eluent to give 2.0 g of compound 4 as a white foam.

LRMS nilz = 412 (M+H) + Title Compound: A solution of compound 4 (1.9g ; 4.6 mmol) in anhydrous dichloromethane (50 mL) was treated with trifluoroacetic acid (50 mL) at room temperature. After stirring for 19 h the reaction mixture was made basic (pH = 12) with 6 N NaOH and additional dichloromethane (100 mL) was added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated to give 1.4 g of the title compound as a white foam that was used without additional purification. LRMS inlz = 312 (M+H) + EXAMPLE 654 3-Amino-pyrazine-2-carboxylic acid [4- (3-fluoro-phenyl)- piperidin-4-ylmethyl]-amide Synthesis F YCN OCN CI CI ci CN CN BoC20 f ci H iPr2NEt NaH H CH2CI2 O O DMF O O 2 3 2 F NH2 F H02CN I O NH II I 2 H2 NH NJ NN H INI J Pt0 /BOP 4 AcOHIEtOH O O F F 0 NH2 O NH2 4 N HCI/dioxane \ HN NU THF N H 6 H 6

Compound 1: Compound 1 is commercially available.

Compound 2: Compound 1 (5.0 g, 28.0 mmol) was suspended in 100 mL of dichloromethane. Di-tert-butyl dicarbonate (6.1 g, 28.0 mmol) and diisopropylethylamine (10.7 mL, 61.6 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (300 mL), washed with IN hydrochloric acid (2 x 100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and saturated aqueous sodium chloride (100 mL). The organic layer was dried (sodium sulfate) and concentrated. The crude residue was purified by silica gel chromatography using 9: 1 hexane: diethyl ether as eluent to give 3.46 g of compound 2 as a colorless oil.

Compound 3: Sodium hydride (1.9 g, 79.0 mmol) was suspended in dimethylformamide (30 mL) and cooled to 0°C. 3-Fluorophenylacetonitrile (2.61 g, 19.3 mmol) was slowly added followed by the addition of compound 2 (3.68 g, 15.2 mmol) as a solution in dimethylformamide (30 mL). The reaction was stirred at 0°C

for 0.5 hours and was allowed to warm to room temperature and stirred overnight.

The reaction mixture was poured into ice and extracted with ethyl acetate (200 mL).

The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The organic layers were combined and washed with 10% lithium chloride (2 x 100 mL), dried (sodium sulfate), filtered and concentrated. The crude residue was purified by flash chromatography on silica gel using 9: 1 hexane: ethyl acetate as the eluent to give 4.04 g of compound 3 as a yellow oil. 1H NMR (CDC13) 61. 48 (9H, s), 1.92 (2H, td, J = 4.3, 13.1), 2.05 (2H, t, J = 10.2), 3.19 (2H, t, J = 12.4), 4.29 (2H, d, J = 13.7), 7. 01- 7.45 (4H, m). LRMS m/z 305 (M+H) +.

Compound 4: Compound 3 (4.04 g, 13.27 mmol) in 50 mL of 15% acetic acid in ethanol was treated with platinum (IV) oxide (0.210 g, 0.925 mmol) and hydrogenated at 60 psi (Parr Apparatus) for 48 h. The reaction mixture was filtered through a thick pad of celite and concentrated. To the concentrate was added 200 mL of diethyl ether and the organic solution was washed with 1N sodium hydroxide (2 x 50 mL) and dried (sodium sulfate), filtered and concentrated to give 4.07 g of compound 4. LRMS into 309 (M+H) +.

Compound 5: To compound 4 (0.562 g, 1.94 mmol) in 15 mL of tetrahydrofuran was added 3-aminopyrazine-2-carboxylic acid (0.270 g, 1.94 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexaf luorophosphate (0.858 g, 1.94 mmol) and triethylamine (0.271 mL, 1.94 mmol). The reaction mixture was stirred for 2 hours at room temperature then diluted with diethyl ether (50 mL), washed with water (3 x 50 mL), saturated sodium chloride (50 mL) and dried over sodium sulfate. After filtration, the solvent was removed by rotary evaporation and the crude residue was purified using flash chromatography (1: 1 hexane/diethyl ether) to give 0.69 g of compound 5. LRMS m/z 430 (M+H) +.

Title Compound: Compound 5 (0.691 g, 1.61 mmol) was suspended in tetrahydrofuran (5 mL) and 4 N hydrochloric acid in 1,4-dioxane (5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, dissolved in water (15 mL) and the aqueous layer was washed with diethyl ether (2 x 15 mL). 6 N Sodium hydroxide was added to basify the aqueous layer that was then extracted with dichloromethane (3 x 20 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated to give 0.47 g of the

title compound as a yellow solid which was used without addtitiona purification.

LRMS m/z 330 (M+H) +.

EXAMPLES 655 TO 695 Examples 655-695 were synthesized using methodology described in Example 1 and Example 654. Example Structure Name M+H 655 F 3-Amino-pyrazine-2-carboxylic 422 acid [1-benzyl-4- (4-fluoro- WJ O NH2 phenyl)-piperidin-4-ylmethyl]- N N ainide N, 656 WF O Oz N-[l-Benzyl-4-(2-fluoro-450 XN Jw phenyl)-piperidin-4-ylmethyl]-2- H hydroxy-6-methoxy-benzamide HO N 657 F o o'N- [4- (2-Fluoro-phenyl)- 343 piperidin-4-ylmethyl]-2- t 0 H 1 methoxy-benzamude N H 658 i F O o'N- [4- (2-Fluoro-phenyl)- 359 piperidin-4-ylmethyl]-2- H hydroxy-6-methoxy-benzaniide N HOB N H 659 Cl 1-Benzoyl-4- (3-chloro-phenyl)- 326 piperidine-4-carbonitrile ZON NEZ --,-a Example Structure Name M+H 660 F 1-Benzoyl-4- (2, 5-difluoro- 327 F N phenyl)-piperidine-4-carbonitrile NEZ "tu i 6610C- [l-Benzyl-4- (3-chloro-316 phenyl)-piperidin-4-yl]- wNH2 methylamine N N i 662 Cl N- [l-Benzyl-4- (3-chloro- 450 o O O'phenyl)-piperidin-4-ylmethyl]-2- N methoxy-benzamide H-1-b N r 663 Cl N-[l-Benzyl-4-(3-chloro-466 O O'phenyl)-piperidin-4-ylmethyl]-2- N hydroxy-6-methoxy-benzamide J ho H N 664 Cl 3-Amino-pyrazine-2-carboxylic 437 O NH2 acid [1-benzyl-4- (3-chloro- NON phenyl)-piperidin-4-ylmethyl]- H amide N in 665 Cl N- [4- (3-Chloro-phenyl)- 360 O O'piperidin-4-ylmethyl]-2- XH Jel methoxy-benzamide JH i N H Example Structure Name M+H 666 C ! N- [4- (3-Chloro-phenyl)- 376 O O'piperidin-4-ylmethyl]-2- N hydroxy-6-methoxy-benzamide il6 H H H 667 ci 3-Amino-pyrazine-2-carboxylic 347 0 NH2 acid [4- (3-chloro-phenyl)- piperidin-4-ylmethyl]-amide rj H IL 'H NJ N H 668 <'4-Cyano-4-(2, 5-difluoro-323 F< N phenyl)-piperidine-1-carboxylic acid tert-butyl ester N IJ< 00 669 F 4-Cyano-4- (3-fluoro-phenyl)- 305 piperidine-l-carboxylic acid tert- butyl ester 1' ! oo< 670 F 4-Aminomethyl-4- (3-fluoro- 309 4 phenyl)-piperidine-1-carboxylic NH2 acid tert-butyl ester N ! F 671 F 4- (3-Fluoro-phenyl)-4- [ (2- 444 4 O O'methoxy-benzoylamino)- NJ methyl]-piperidine-1-carboxylic t j H W acidtert-butyl ester T S 0X0~ 672 F N- [4- (3-Fluoro-phenyl)- 343 o O O'piperidin-4-ylmethyl]-2- methoxy-benzamide H N H Example Structure Name M+H 673 sO 3-Amino-pyrazine-2-carboxylic 433 acid [1-benzyl-4- (3-methoxy- O NH2 phenyl)-piperidin-4-ylmethyl]- l'amide H NU ! J H N , c 674 F 4- { [ (3-Amino-pyrazine-2- 430 O NH2 carbonyl)-amino]-methyl}-4- (3- eNXN fluoro-phenyl)-piperidine-1- ri j H Nsd carboxylic acid tert-butyl ester N 0 675 sO 3-Amino-pyrazine-2-carboxylic 342 0 NH2 acid [4- (3-methoxy-phenyl)- piperidin-4-ylmethyl]-amide non H ! N H 676 F 3-Amino-pyrazine-2-carboxylic 330 O NH2 acid [4- (3-fluoro-phenyl)- XJ+NXN piperidin-4-ylmethyl]-amide H N N H 677 F 4-Aminomethyl-4- (2, 5-difluoro- 327 F NH2 phenyl)-piperidine-l-carboxylic acid tert-butyl ester N 0X0k 678 F O O'4-(2, 5-Difluoro-phenyl)-4-[(2-462 F N methoxy-benzoylamino)- H-1-b methyl]-piperidine-l-carboxylic acid tert-butyl ester 0X02\ 679 F o o'4- (2, 5-Difluoro-phenyl)-4- [ (2- 478 F N hydroxy-6-methoxy- benzoylamino)-methyl]- N Ho piperidine-l-carboxylic acid tert- butyl ester Example Structure Name M+H 680 F 0 NH2 4-f [ (3-Amino-pyrazine-2- 448 F<N XN carbonyl)-amino]-methyl}-4- 0) H N (2, 5-difluoro-phenyl)-piperidine- 1-carboxylic acid tert-butyl ester ORoJ< 681 F o o'N- [4- (2, 5-Difluoro-phenyl)- 361 F N piperidin-4-ylmethyl]-2- 0 0 H lX methoxy-benzamide N H 682 SF O NH2 3-Amino-pyrazine-2-carboxylic 348 acid [4- (2, 5-difluoro-phenyl)- 3y, piperidin-4-ylmethyll-amide N N H 683 n O On 2, 3-Dihydro-benzofuran-7- 428 N carboxylic acid (l-benzyl-4- phenyl-piperidin-4-ylmethyl)- "N amide N 684 n O O'N-(l-Benzyl-4-phenyl-piperidin-450 vNA 4-ylmethyl)-5-chloro-2- H methoxy-benzamide ci 685 o'N- [I-Benzyl-4- (3-methoxy- 446 'phenyl)-piperidin-4-ylmethyl]-2- O O methoxy-benzamide 'N 1 ; 1 H Ji N X 686 0""2-Methoxy-N- [4- (3-methoxy- 355 O O'phenyl)-piperidin-4-ylmethyl]- benzamide N J Hz N H Example Structure Name M+H 687 n O o'N-(l-Benzyl-4-phenyl-piperidin-432 N 4-ylmethyl)-2-hydroxy-6- H methoxy-benzamide HOB N 688 o o'2-Hydroxy-6-methoxy-N- (4- 341 VXN V phenyl-piperidin-4-ylmethyl)- N j HOX benzamide MU H N H 689 i O 0'4-(3-Fluoro-phenyl)-4-[(2-460 F N hydroxy-6-methoxy- H benzoylarino)-methyl]- L J t-tf N HO piperidine-1-carboxylic acid tert- oSoJ< butyl ester 690 SF o ow N-[l-Benzyl-4-(2-fluoro-434 N phenyl)-piperidin-4-ylmethyl]-2- methoxy-benzamide N i 691 F 4- (3, 5-Difluoro-phenyl)-4- [ (2- 478 O O'hydroxy-6-methoxy- F N benzoylamino)-methyl]- H piperidine-1-carboxylic acid tert- N butyl ester 0-0 692 F 4-1 [ (3-Amino-pyrazine-2- 448 O NH2 carbonyl)-amino]-methyl}-4- F-J@N) N (3, 5-difluoro-phenyl)-piperidine- H N 1-carboxylic acid tert-butyl ester N 693 F o O 4- [ (2-Hydroxy-6-methoxy- 510 F N benzoylamino)-methyl]-4- (3- F H trifluoromethyl-phenyl)- N piperidine-1-carboxylic acid tert- 0, butyl ester Example Structure Name M+H 694 F n O NH2 4-{[(3-Amino-pyrazine-2-481 F< NXI N carbonyl)-amino]-methyl}-4-(3- trifluoromethyl-phenyl)- JF N piperidine-l-carboxylic acid tert- butyl ester 695 F o o'4- [ (2-Methoxy-benzoylamino)- 494 F-N methyl]-4- (3-trifluoromethyl- F t 0 H IXJ phenyl)-piperidine-l-carboxylic N acid tert-butyl ester o'Ok EXAMPLE 696

N-(1-Cyclohexylsulfamoyl-4-phenyl-piperidin-4-ylmethyl)-2-me thoxy-benzamide Synthesis

Compound 1: Compound 1 was prepared as described in Example 15.

Compound 2: Compound 2 was prepared as described in J. Org. Che7n.

2003, 68, 115-119.

Compound 3: Compound 2 (3.34 g, 8.6 mmol) was suspended in 15 mL of acetonitrile and cooled to 0°C. Compound 1 (2.14 g, 6.6 mmol) was slowly added.

The reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated and purified directly by flash chromatography on silica gel using 3: 1 ethylacetate/hexane as the eluent to give 1.92 g of compound 3. LRMS nilz 469 (M+H) +.

Compound 4: Compound 3 (1.9 g, 4.05 mmol) was suspended in 16 mL of dichloromethane and cooled to 0°C. A solution of methyl triflate (0.505 mL, 4.46 mmol) in dichloromethane (16 mL) was slowly added. The reaction was allowed to warm to room temperature, stirred for 2 h and concentrated. Compound 4 was used in the next step without further purification. LRMS nilz 483 (M+H) +.

Title Compound: To compound 4 (0.075 g, 0.118 mmol) and cyclohexylamine (0.016 mL, 0.142 mmol) was added 0.695 mL of acetonitrile. The reaction mixture was heated to 80°C for 4 h and concentrated. The crude material was purified using preparative reverse phase HPLC to give 0.026 g of the title compound as a white solid. LRMS m/z 488 (M+H) +.

EXAMPLES 697 TO 843 Examples 697 to 843 were prepared using methodology described in Example 15, Example 16, Example 17 and Example 696. Example Structure Name M+H 697 0 4-Phenyl-l-sulfamoyl-390 XN> piperidine-4-carboxylic acid benzyl-methyl-amide N o=s=o H, 698 0 1- (4-Fluoro- 498 benzylsulfamoyl)-4-phenyl- piperidine-4-carboxylic acid N benzyl-methyl-amide O=S=O H F F 699 i I p i I 4-Phenyl-1-sulfamoyl-457 KJT NAF piperidine-4-carboxylic acid H F F [2- (3-trifluoromethyl- NJ phenyl)-ethyl]-amide O=S=O NH2 700 0 1- (4-Fluoro- 566 XNX benzylsulfamoyl)-4-phenyl- 1 H F F piperidine-4-carboxylic acid IN [2- (3-trifluoromethyl- O=S=O phenyl)-ethyl]-amide HO F 701 o O O'N-[l-(Imidazole-l-sulfonyl)-457 4-phenyl-piperidin-4- H-"-b ylmethyl]-2-methoxy- IN benzamide O=S=O N . N Example Structure Name M+H 702 0 4-Phenyl-l-sulfamoyl-452 WN+rw piperidine-4-carboxylic acid H (biphenyl-3-ylmethyl)-amide ION O=S=O NH2 703 i I p i I 1- (4-Fluoro- 560 N benzvlsulfamoyl)-4-phenyl- H piperidine-4-carboxylic acid N (biphenyl-3-ylmethyl)-amide O=S=O HN H F 704 n O O'N-(4-Cyclohex-l-enyl-1-438 w N A dimethylsulfamoyl- t 1 H CJ piperidin-4-ylmethyl)-2- IN methoxy-benzamide i Q. O I i 705 I O O'N-(4-Cyclohex-l-enyl-1-468 N dimethylsulfamoyl- t 0 H O/piperidin-4-ylmethyl)-2, 4- IN dimethoxy-benzamide Is, . O I i 706 n O N- (4-Cyclohex-l-enyl-l- 468 vNXYX dimethylsulfamoyl- piperidin-4-ylmethyl)-2, 6- dimethoxy-benzamide O, S. NEZ 0, 61 707 t F N-(4-Cyclohex-l-enyl-1-492 n O F dimethylsulfamoyl- v N) + piperidin-4-ylmethyl)-2- t W trifluoromethoxy-benzamide IN off Example Structure Name-M+H 708 0 F N- (4-Cyclohex-l-enyl-l- 426 XN) + dimethylsulfamoyl- H piperidin-4-ylmethyl)-2- fluoro-benzamide Is OvlO/ 709 JA 4-Cyclohex-1-enyl-4- [(2-528 < O F trifluoromethoxy- N'benzenesulfonylamino)- H methyl]-piperidine-l- IN sulfonic acid dimethylamide Off ou 710 F 4-Phenyl-4- [ (2- 496 0 F trifluoromethoxy- XNSS benzenesulfonylamino)- methyl]-piperidine-1- N sulfonic acid amide i O=S=O NH2 711 F 4-Phenyl-4-[(2-604 0 F trifluoromethoxy- WJ+N\SS benzenesulfonylamino)- 0 3 H td methyl]-piperidine-l- N sulfonic acid 4-fluoro- O=S=O benzylamide HN) F 712 < O O'5-Chloro-2-methoxy-N- (4- 440 phenyl-1-sulfamoyl- H piperidin-4-ylmethyl)- benzamide O=S=O NH2 Example Structure Name M+H 713 i I O O'S-Chloro-N- [1- (4-fluoro- 548 benzylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- IN methoxy-benzamide O=S=O H F 714 n O n 4-Phenyl-l-sulfamoyl-472 N w F piperidine-4-carboxylic acid F F methyl- [2- (3- IN trifluoromethyl-phenyl)- O= IS=O ethyl]-amide NH2 715 n O n 1-(4-Fluoro-580 F benzylsulfamoyl)-4-phenyl- F F piperidine-4-carboxylic acid methyl- [2- (3- O=S=O trifluoromethyl-phenyl)- HN ethyl]-amide F 716 n O On 2, 3-Dihydro-benzofuran-7- 418 N carboxylic acid (4-phenyl-1- H sulfamoyl-piperidin-4- ylmethyl)-amide O=S=O NH2 717 W O On 2, 3-Dihydro-benzofuran-7- 526 N carboxylic acid [1- (4-fluoro- H benzylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-amide i O=S=O H F Example Structure Name M+H 718 O I O O'N- [4- (3, 6-Dihydro-2H- 440 XNv pyran-4-yl)-1- t J H IXJ dimethylsulfamoyl- piperidin-4-ylmethyl]-2- SNOO methoxy-benzamide b 719 S o O'2-Methoxy-N-(l-sulfamoyl-412 NJ, 6 4-thiophen-3-yl-piperidin-4- H ylmethyl)-benzamide ION O=S=O NUS 720 o c, N- [4- (4-Fluoro-phenyl)-l- 423 sulfamoyl-piperidin-4- H ylmethyl]-2-methoxy- IN benzamide O=S=O NH2 721 4- [ (4-Methyl-pyridin-2- 391 N'a ylamino)-methyl]-4-phenyl- H piperidine-l-sulfonic acid IN dimethylamide 0vot' 722 F N- [4- (3-Fluoro-phenyl)-l- 423 O O'sulfamoyl-piperidin-4- VXN JA ylmethyl]-2-methoxy- X j H 19 benzamide ION 0=v=0 NH2 t\ ! H2 723 n O F N-(l-Dimethylsulfamoyl-4-422 N phenyl-piperidin-4- H ylmethyl)-2-fluoro- IN benzamide O=S=O °41-° 724 n O O'2, 3-Dimethoxy-N-(4-phenyl-436 vN) <O 1-sulfamoyl-piperidin-4- ylmethyl)-benzamide ION O=S=O NH2 f\ ! H2 Example Structure Name M+H 725 F O O'N- [4- (2-Fluoro-phenyl)-1- 423 sulfamoyl-piperidin-4- H ylmethyl]-2-methoxy- IN benzamide i 0=3=0 _ 726 o o'2-Methoxy-N- {4-phenyl-l- 497 N'k'6 [ (pyridin-2-yli-nethyl)- H sulfamoyl]-piperidin-4- IN ylmethyl}-benzamide , S, p ON 727 0 (Dr'2-Methoxy-N- [4- (3- 436 methoxy-phenyl)-1- sulfamoyl-piperidin-4- p ylmethyl l-benzamide (ys-, WF ? 2 728 n O O'Carbamic acid 2-{4-[(2-493 wNJ4f A methoxy-benzoylamino)- t | H W methyl]-4-phenyl-piperidine- N 1-sulfonylamino}-ethyl ester i O=S=O 0 HNp-NH2 729 o o p'Ethyl-carbamic acid 2- {4- 521 <\N v [(2-methoxy-benzoylamino)- t 0 W methyl]-4-phenyl-piperidine- 1-sulfonylamino}-ethyl ester O=S=O 0 HA H 730 o'o 2-Methoxy-N- [4-phenyl-l- 511 N'j6 (2-pyridin-4-yl- t 0 H 1X1 ethylsulfamoyl)-piperidin-4- N IN ylmethyll-benzamide N OO H N'§70 731 F N- (4-Phenyl-l-sulfamoyl- 459 O O F piperidin-4-ylmethyl)-2- tN X trifluoromethoxy-benzamide H ION O=S--O NH2 Example Structure Name M+H 732 o o O'2, 6-Dimethoxy-N- (4-phenyl- 436 N 1-sulfamoyl-piperidin-4- H ylmethyl)-benzainide 0 IN o=s=o NH2 733 n O O'Cyclopropyl-carbamic acid 533 N 2- {4- [ (2-methoxy- t J W benzoylamino)-methyl]-4- N phenyl-piperidine-1- O=S=O 0 sulfonylamino}-ethyl ester HNN H 734 n o 2-Methoxy-N- [l- (2-methyl- 471 N'l"d iniidazole-l-sulfonyl)-4- t 3 H W phenyl-piperidin-4- ylmethyl]-benzamide O=S=O N AND 735 n O O'2-Methoxy-N-(1-420 < N) + methylsulfamoyl-4-phenyl- H piperidin-4-ylmethyl)- benzamide O=S=O His 736 n O O'N-(l-Ethylsulfamoyl-4-434 N phenyl-piperidin-4- ylmethyl)-2-methoxy- benzamide 0--S=O HO 737 n O O'N-(l-Cyclopropylsulfamoyl-446 N 4-phenyl-piperidin-4- H ylmethyl)-2-methoxy- benzamide 0==0 H Hh, V Example Structure Name M+H 738 o O O'2-Methoxy-N-{4-phenyl-1-490 N [ (tetrahydro-furan-2- 0 j H W ylmethyl)-sulfamoyl]- p O piperidin-4-ylmethyl}- O\^N, S O benzamide H 739 n O O'N-[l-(Isopropyl-methyl-462 <NJA sulfamoyl)-4-phenyl- t j H 1 piperidin-4-ylmethyl]-2- NN methoxy-benzamide 0=S=0 zu i 740 n O O'2-Methoxy-N- {4-phenyl-1- 497 KJXN A [(pyridin-3-ylmethyl)- H sulfamoyl]-piperidin-4- N ylmethyl}-benzamide O=S=O HN Hi 6 741 n O O'2-Methoxy-N-{4-phenyl-1-497 <NJA [(pyridin-4-ylmethyl)- H sulfamoyl]-piperidin-4- NN ylmethyl}-benzamide O=S=O HN N 742 o O O'N- [1- (2-Hydroxy- 464 N propylsulfamoyl)-4-phenyl- t j H 1 piperidin-4-ylmethyl]-2- g methoxy-benzamide 0=S=0 HAN OH Example Structure Name M+H 743 n O O (2- {4- [ (2-Methoxy- 549 ,---N benzoylamino)-methyll-4- 0 X H W phenyl-piperidine-l- sulfonylamino}-ethyl)- O=S=O carbamic acid tert-butyl ester HO "NH x 744 n O O'N-{1-[(2-Hydroxy-ethyl)-464 N I methyl-sulfamoyl]-4-phenyl- piperidm-4-ylmethyl}-2- methoxy-benzamide 0=S=0 OU 745 fB O O'N-(l-Dimethylsulfamoyl-4-435 phenyl-piperidin-4- H ylmethyl)-2-methoxy- nicotinamide N O=S=O 7 6 n O tA Quinoline-8-carboxylic acid 455 (1-dimethylsulfamoyl-4- (0 H lW phenyl-piperidin-4- IN ylmethyl)-amide i O=S=O 747 747 o o'N- [I- (Cyclopropylmethyl- 460 sulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide zon O=S=O HAN Example Structure Name M+H 748 Q N- [l- (3-Hydroxy- 476 pyrrolidine-1-sulfonyl)-4- H phenyl-piperidin-4- IN ylmethyl]-2-methoxy- O=S=O benzamide C HO 749 o o N- [l- (2-Dimethylamino- 477 N ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide ION O=S=O HO H 750 0- N- [l- (2-Fluoro- 452 ethylsulfamoyl)-4-phenyl- H piperidin-4-ylmethyl]-2- methoxy-benzamide ION O=S=O H JF 751 Q o N- [l- (CarbamoyImethyI- 463 sulfamoyl)-4-phenyl- t 0 H lW piperidin-4-ylmethyl]-2- N methoxy-benzamide O=S=O HN CfNHs 752 Q o- l- {4- [ (2-Methoxy-503 N benzoylamino)-methyl]-4- H phenyl-piperidine-l- N sulfonyl}-pyrrolidine-2- carboxylic acid amide / N VJ NH2 Example Structure Name M+H 753 o O'N-(l-Isopropylsulfamoyl-4-448 phenyl-piperidin-4- N Y H ylmethyl)-2-methoxy- benzamide N O=S=O H 754 po 0N- [l- (2-Amino-449 N ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- N methoxy-benzamide O=S=O HN H INH2 755 n O O'2-Methoxy-N-{4-phenyl-1-527 N'l"b [2- (pyrimidin-2-ylamino)- H ethylsulfamoyl]-piperidin-4- N ylmethyl}-benzamide O=S=O H INH "NH u 756 o O O'2-Methoxy-N- {4-phenyl-1- 541 N'jb [3- (pyrimidin-2-ylarnino)- H propylsulfamoyl]-piperidin- IN 4-ylmethyl}-benzamide O=0S-O Ht HAN N 757 i O O'2-Methoxy-N- [4-phenyl-1- 483 (pyridin-4-ylsulfamoyl)- H piperidin-4-ylmethyl]- NJ benzamide O=S=O , N N i -| Example Structure Name 758 o or'2-Methoxy-N- [4-phenyl-l- 483 w I N I (pyridin-3-ylsulfamoyl)- H piperidin-4-ylmethyl]- IN benzamide O=S=O HO SU 759 n O O 2-Methoxy-N- [4-phenyl-1- 483 N (pyridin-2-ylsulfamoyl)- H piperidin-4-ylmethyl]- IN benzamide O=S=O HAN Dz 760 n o'N- [I- (4-Hydroxy-piperidine- 490 w NJ n 1-sulfonyl)-4-phenyl- H piperidin-4-ylmethyl]-2- IN methoxy-benzamide 0=S=O OU OH 761 o o'N- [I- (3, 4-Difluoro- 518 N'rad phenylsulfamoyl)-4-phenyl- 0 j H lW piperidin-4-ylmethyl]-2- N methoxy-benzamide i O=S=O HZ kip F 762 o o,-'N-11- (2, 4-Difluoro- 518 X NJ A phenylsulfamoyl)-4-phenyl- t j H 1 piperidin-4-ylmethyl]-2- IN methoxy-benzamide i O=S=O Ho F F Example Structure Name M+H 763 o O O'2-Methoxy-N-(4-phenyl-1-482 N phenylsulfamoyl-piperidin- t j H W 4-ylmethyl)-benzamide IN O=S=O HNo __ i 764 o or'N- [I- (2-Hydroxy- 464 N propylsulfamoyl)-4-phenyl- V) H W piperidin-4-ylmethyl]-2- IN methoxy-benzamide O=S O -OH 765 n O p N- [1- (2-Hydroxy-1-methyl- 464 w NJA ethylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- IN methoxy-benzamide O=S=O n 766 o O O'N-[l-(l-Hydroxymethyl-478 N propylsulfamoyl)-4-phenyl- H piperidin-4-ylmethyl]-2- IN methoxy-benzamide 0--S=O HO PI roh 767 n O O'N- [1- (2-Hydroxy- 464 N propylsulfamoyl)-4-phenyl- t j H W piperidin-4-ylmethyl]-2- NN methoxy-benzamide O=S=O HNJ-.. OH 768 o O O'N-[l-(l-Hydroxymethyl-478 N propylsulfamoyl)-4-phenyl- H piperidin-4-ylmethyl]-2- IN methoxy-benzamide O=S=O HN3ßOH Example Structure Name M+H 769 N- [I- (2-Hydroxy-l-methyl- 464 vaN m ethylsulfamoyl)-4-phenyl- t 0 H W piperidin-4-ylmethyl]-2- methoxy-benzamide OXO roH 770 o 0', 2-Methoxy-N- [l- (2- 526 phenoxy-ethylsulfamoyl)-4- phenyl-piperidin-4- N ylmethyl l-benzamide O=S=O HN po l 771 o or'14- [ (2-Methoxy- 478 wNJ benzoylamino)-methyl]-4- H phenyl-piperidine-l- sulfonylamino}-acetic acid O=S=O methyl ester HAN HN ouzo 772 n o 2-14- [ (2-Methoxy- 492 wNA benzoylamino)-methyl]-4- H phenyl-piperidine-l- sulfonylamino}-propionic O=S=O acid methyl ester H 773 n O O'2-{4-[(2-Methoxy-568 N benzoylamino)-methyl]-4- phenyl-piperidine-l- sulfonylamino}-3-phenyl- O=S=O O'propionic acid methyl ester HNoßo Example Structure Name M+H 774 i o O N- (I-DimethylsuIfamoyl-4- 450 N phenyl-piperidin-4- H ylmethyl)-2-hydroxy-6- methoxy-benzamide O=S=O Ns 775 o O O'N-(l-Dimethylsulfamoyl-4-452 XN A phenyl-piperidin-4- H ylmethyl)-2-fluoro-6- N F methoxy-benzamide O=IS=O No 776 F 2-DiQuoromethoxy-N- (l- 470 O OF dimethylsulfamoyl-4-phenyl- X N<f S piperidin-4-ylmethyl)- benzamide ION o=s=o "hl- 777 0 NH2 3-Amino-pyrazine-2-421 carboxylic acid (1- t j H N, dimethylsulfamoyl-4-phenyl- J N piperidin-4-ylmethyl)-amide O=S=O , N, 778 i O O° N- [1- (4-Fluoro- 500 vXN v phenylsulfamoyl)-4-phenyl- t) H W piperidin-4-ylmethyl]-2- _ methoxy-benzamide O=S=O HO F F 779 n O O'2-Methoxy-N-[l-(methoxy-450 vx<N A methyl-sulfamoyl)-4-phenyl- 06H piperidin-4-ylmethyl]- benzamide O=S-O N. O° Example Structure Name M+H 780 O O'N- (l-Hydroxysulfamoyl-4- 422 phenyl-piperidin-4- H ylmethyl)-2-methoxy- NJ benzamide O=S=O HN. OH 781 O N- [l- (2-Fluoro- 500 N phenylsulfamoyl)-4-phenyl- 0 3 H 1 piperidin-4-ylmethyl]-2- IN methoxy-benzamide O=S=O Hin i F 782 o (3, N- [I- (3-Fluoro- 500 N phenylsulfamoyl)-4-phenyl- C 0 H W piperidin-4-ylmethyl]-2- IN methoxy-benzamide O=S=O han F F 783 < O O'N-[l-(l, l-Dioxo-tetrahydro-524 N'1'6 1 lambda* 6*-thiophen-3- t j H 1 ylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- O= methoxy-benzamide HO 0 784 p O N- [1- (4-Hydroxymethyl- 504 N,I piperidine-1-sulfonyl)-4- H phenyl-piperidin-4- ylmethyl]-2-methoxy- O=S=O benzamide N HA Example Structure Name M+H 785 o O 0 N- {H (2-Pluoro-phenyl)- 514 N) t6 methyl-sulfamoyl]-4-phenyl- piperidin-4-ylmethyl}-2- methoxy-benzamide O=S=O N I w .. 786 o o, 0N- {l- [ (3-Fluoro-phenyl)-514 methyl-sulfamoyl]-4-phenyl- piperidin-4-ylmethyl}-2- methoxy-benzamide O=S=O N i F 787 o O O'N-[l-(Hydroxy-methyl-436 sulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- N methoxy-benzamide °41 =° 'OH 788 o o'2-Methoxy-N- (I- 419 X N A methylsulfamoyl-4-phenyl- H piperidin-4-ylmethyl)- benzamide O-S=O Ht, 789 n O O'N-(l-tert-Butylsulfamoyl-4-462 N phenyl-piperidin-4- H ylmethyl)-2-methoxy- benzamide O=S=O f 790 o O O'N- [1- (4, 4-Dimethyl- 490 oxazolidine-3-sulfonyl)-4- phenyl-piperidin-4- ç ylmethyl]-2-methoxy- 0=S=0 benzamide N O Example Structure Name M+H 791 n O O'N-[1-(2, 6-Dimethyl-504 wN morpholine-4-sulfonyl)-4- phenyl-piperidin-4- IN ylmethyl]-2-methoxy- O=S=O benzamide N O 792 n or'N- [I- (4, 4-Dimethyl-4, 5- 487 w NJ A dihydro-imidazole-1- H sulfonyl)-4-phenyl- X piperidin-4-ylmethyl]-2- O=S=O methoxy-benzamide N Nt 793 o o'N- [I- (2-Hydroxy-1, 1- 478 vNv dimethyl-ethylsulfamoyl)-4- H phenyl-piperidin-4- ç ylmethyl]-2-methoxy- 0--S=O benzamide HAN SOH 794 o o'N- [I- (4-Hydroxy- 512 </9NAYX benzylsulfamoyl)-4-phenyl- t 1 H W piperidin-4-ylmethyl]-2- methoxy-benzamide O=S=O HN OH OH 795 n O O'N- [1- (3-Hydroxy- 498 N phenylsulfamoyl)-4-phenyl- H piperidin-4-ylmethyl]-2- methoxy-benzamide O=S=O y OH OH Example Structure Name M+H 796 n O O'N-[1-(2-Hydroxy-504 N cyclohexylsulfamoyl)-4- H phenyl-piperidin-4- ç ylmethyl]-2-methoxy- O=S=OOH benzamide Han,,",, 797 o o,-'2-Methoxy-N- [l- (2- 504 bJ<'N v methoxymethyl-pyrrolidine- C 3 H X l-sulfonyl)-4-phenyl- ç piperidin-4-ylmethyl]- O=S=O benzamide N zou 798 n O N- [I- (I-Hydroxymethyl-2- 492 N methyl-propylsulfamoyl)-4- H phenyl-piperidin-4- C ylmethyl]-2-methoxy- 0=S=0 benzamide HO OH 799 < O O'N-[l-(l-Hydroxymethyl-2-492 N methyl-propylsulfamoyl)-4- phenyl-piperidin-4- W ylmethyl]-2-methoxy- 0=S=O benzamide HNX,, OH fi 800 o o'N- [I- (2-Cyclohexyl-l- 546 N hydroxymethyl- H ethylsulfamoyl)-4-phenyl- IN piperidin-4-ylmethyl]-2- O=S=O methoxy-benzamide HAN HO 801 o o'N- [I- (2-Hydroxy-indan-l- 538 ylsulfamoyl)-4-phenyl- C 3 H W piperidin-4-ylmethyll-2- p methoxy-benzamide H n 0--S=O Ho,".. \ I HO Example Structure Name M+H 802 n o-'N- [I- (2-Hydroxy-indan-l- 538 ylsulfamoyl)-4-phenyl- piperidin-4-ylmethyl]-2- methoxy-benzamide O=S=O HO HA 803 n O 6 N- [I- (3-Hydroxy- 476 pyrrolidine-1-sulfonyl)-4- H phenyl-piperidin-4- ylmethyl]-2-methoxy- 0=8=0 benzamide N Hop 804 1-f4- [ (2-Methoxy- 518 benzoylamino)-methyl]-4- H phenyl-piperidine-l- IN sulfonyl}-pyrrolidine-2- 0=S=O O carboxylic acid methyl ester t 0 805 n O O'2-{4-[(2-Methoxy-520 benzoylamino)-methyl]-4- H phenyl-piperidine-l- sulfonylamino}-3-methyl- t butyric acid methyl ester Han"", 806 < 2-Hydroxy-6-methoxy-N- {1-494 O OH [ (2-methoxy-ethyl)-methyl- w sulfamoyl]-4-phenyl- H O i piperidin-4-ylmethyl}- benzamide 807 n 2-Hydroxy-6-methoxy-N-(4-422 9 O OH phenyl-l-sulfamoyl- piperidin-4-ylmethyl)- H O_b benzamide 00 P Example Structure Name M+H 808 F N- [4- (3-Fluoro-phenyl)-1- 439 o O O'sulfamoyl-piperidin-4- N ylmethyl]-2-hydroxy-6- H2Ns, NJ HHOX methoxy-benzamide s HO6 6b 809 N- [4- (3-Fluoro-phenyl)-l- 505 ! O' (2-methyl-imidazole-1- C NA sulfonyl)-piperidin-4- N, N, N H ylmethyll-2-hydroxy-6- methoxy-benzamide 810 F N- [4- (3-Fluoro-phenyl)-l- 484 t S O 0' (2-hydroxy-ethylsulfamoyl)- H/\/Nv piperidin-4-ylmethyl]-2- Ho~N, N HO'hydroxy-6-methoxy- O"ssso benzamide 811 F N- [l- (Cyclopropylmethyl- 494 O O'sulfamoyl)-4- (3-fluoro- H N phenyl)-piperidin-4- >Ns, N HO) ylmethyl]-2-hydroxy-6- HO methoxy-benzamide 812 N- [4- (3-Fluoro-phenyl)-l- 534 O O' (4-fluoro-phenylsulfamoyl)- H N piperidin-4-ylmethyl]-2- N, N NJ H oJW hydroxy-6-methoxy- OS, O HO benzamide 0 0 813 F N- [4- (3-Fluoro-phenyl)-1- 546 Ho (4-hydroxy- , H eHM benzylsulfamoyl)-piperidin- H 1 H 4-ylmethyl]-2-hydroxy-6- methoxy-benzamide 814 F N- [4- (3-Fluoro-phenyl)-1- 498 O O' (2-hydroxy-1-methyl- H N ethylsulfamoyl)-piperidin-4- N,, N H ylmethyl]-2-hydroxy-6- methoxy-benzamide 815 F N- [4- (3-Fluoro-phenyl)-l- 512 O O' (1-hydroxymethyl- H N propylsulfamoyl)-piperidin- Ho % Ns, NJ HO4J 4-ylmethylJ-2-hydroxy-6- O methoxy-benzamide Example Structure Name M+H 816 N- [4- (3-Fluoro-phenyl)-l- 498 o cy' (2-hydroxy- H N propylsulfamoyl)-piperidin- HO Ns, NJ HO) 4-ylmethyl]-2-hydroxy-6- methoxy-benzamide 817 F N- [4- (3-Fluoro-phenyl)-l- 510 W O O' (3-hydroxy-pyrrolidine-1- sulfonyl)-piperidin-4- HO°"N. N H ylmethyl]-2-hydroxy-6- HO methoxy-benzamide 818 o o'2-Hydroxy-6-methoxy-N- [l- 487 N (2-methyl-imidazole-l- H sulfonyl)-4-phenyl- piperidin-4-ylmethyl]- O=S=O benzamide N ----cN 819 011---0 F Trifluoro-669 o o'methanesulfonate3- {4- (3- 1> 1/\/N J fluoro-phenyl)-4-[(2- 'Y HO hydroxy-6-methoxy- benzoylamino)-methyl]- piperidine-1-sulfonyl}-1, 2- dimethyl-3H-imidazol-1- ium ; 820 F N- [4- (3-Fluoro-phenyl)-l- 560 o o' (2-phenoxy-ethylsulfamoyl)- piperidin-4-ylmethyl]-2- HO hydroxy-6-methoxy- benzamide 821 N-14- (3-Fluoro-phenyl)- I-498 W O [ (2-hydroxy-ethyl)-methyl- sulfamoyl]-piperidin-4- HO NU HO ylmethyl}-2-hydroxy-6- H HO methoxy-benzamide 822 F w N- {4- (3-Fluoro-phenyl)-1- 524 W O [ (tetrahydro-furan-2- H N Ylmethyl)-sulfamoyl]- N, NxJ HOX plpendm-4-ylmethyl}-2- hydroxy-6-methoxy- benzamide Example Structure Name M+H 823 | N-(1-Dimethylsulfamoyl-4-420 w O OH phenyl-piperidin-4- I C9Nv ylmethyl)-2-hydroxy- , N H H 1X1 benzamide db 824 F9F N-[l-Dimethylsulfamoyl-4-488 F \ (3-trifluoromethyl-phenyl)- 0 OH piperidin-4-ylmethyl]-2- N hydroxy-benzamide N.. N H db 825 F F N-[l-Dimethylsulfamoyl-4-502 ( (3-trifluoromethyl-phenyl)- 9 O O'piperidin-4-ylmethyl]-2- N methoxy-benzamide I N. S. N H i N H-1-b 826 CF F (D, N- [4- (2-Fluoro-phenyl)-l- 439 sulfamoyl-piperidin-4- ylmethyl]-2-hydroxy-6- HO methoxy-benzamide O=S=O NH2 827 eF O oz N-[l-Dimethylsulfamoyl-4-468 (2-fluoro-phenyl)-piperidin- 4-ylmethyl]-2-hydroxy-6- IN methoxy-benzamide O=S=O "-h-, 828 C ! N- [4- (3-Chloro-phenyl)-l- 440 sulfamoyl-piperidin-4- ylmethyl]-2-methoxy- benzamide ION O=S=O NH2 829 Cl N- [4- (3-Chloro-phenyl)-1- 468 O O'dimethylsulfamoyl- piperidin-4-ylmethyl]-2- methoxy-benzamide IN O=S=O N Example Structure Name M+H 830 F N- [4- (3, 5-Difluoro-phenyl)- 441 O O'l-sulfamoyl-piperidin-4- F + ylmethyl]-2-methoxy- H benzamide 0', IN O'SNH2 831 F N- [4- (3, 5-Difluoro-phenyl)- 470 rA O 0/l-dimethylsulfamoyl- F <\N) + piperidin-4-ylmethyl]-2- H methoxy-benzamide ol IN O'S'N 832 F F N- [4- (3, 5-Difluoro-phenyl)- 457 1-sulfamoyl-piperidin-4- N ylmethyl]-2-hydroxy-6- H2N, N H methoxy-benzamide 'HO OO 833 F F 3-Amino-pyrazine-2-428 i O NH2 carboxylic acid [4- (3, 5- N difluoro-phenyl)-l- sulfamoyl-piperidin-4- ylmethyl]-amide 834 3-Amino-pyrazine-2-392 0 NH2 carboxylic acid (4-phenyl-1- sulfamoyl-piperidin-4- H2N, N H N ylmethyl)-amide 0 0 835 pF 2-Hydroxy-6-methoxy-N- [l- 489 sulfamoyl-4- (3- < 0 O'trifluoromethyl-phenyl)- N piperidin-4-ylmethyl]- H2Ns, N HHO'benzamide HO 836 F F 3-Amino-pyrazine-2-460 carboxylic acid [1- 0 NH2 sulfamoyl-4- (3- N trifluoromethyl-phenyl)- H2Ns, NJ H N piperidin-4-ylmethyl]-amide 0/S0 Example Structure Name M+H 837 ci 3-Amino-pyrazine-2-427 0 NH2 carboxylic acid [4- (3-chloro- N phenyl)-l-sulfamoyl- l-piperidin-4-ylmethyll-amide v 0=S=O NH2 8 3 8 3-Amino-pyrazine-2-410 O NH2 carboxylic acid [4- (3-fluoro- phenyl)-l-sulfamoyl- NN H N J piperidin-4-ylmethyl]-amide H N o=ls-o NH2 839 F o o, N- [4- (2, 5-Difluoro-phenyl)- 441 1-sulfamoyl-piperidin-4- C) H W ylmethyl]-2-methoxy- i IN benzamide i O=S=O NH2 840 wF o NH2 3-Amino-pyrazine-2-428 2 carboxylic acid [4- (2, 5- S N difluoro-phenyl)-l- H NJ IN sulfamoyl-piperidin-4- O=S=O ylmethyl]-amide NH2 841 F F 2-Methoxy-N-[l-sulfamoyl-472 F 4- (3-trifluoromethyl- W O O'phenyl)-piperidin-4- N ylmethyl]-benzamide H2Ns, N J H W 00 842 F N- [4- (2, 3-Difluoro-phenyl)- 440 A/o o l-sulfamoyl-piperidin-4- N ylmethyl]-2-methoxy- benzamide . ion O=S=O NH2 Example Structure Name M+H 843 F 3-Amino-pyrazine-2-427 O NH2 carboxylic acid [4- (2, 3- difluoro-phenyl)-1- NN N-T sulfamoyl-piperidin-4- ylmethyl]-amide O=S=O NH2 EXAMPLE 844

3-Amino-pyrazine-2-carboxylic acid [1- (amino-methanesulfonylimino-methyl)- 4-phenyl-piperidin-4-ylmethyl]-amide Synthesis

Compound 1: Compound 1 was prepared as described in Example 653.

Compound 2: A solution of compound 1 (0.15 g; 0.47 mmol) in anhydrous acetonitrile (8 mL) at room temperature was treated with N-diphenoxymethylene- methanesulfonamide (for preparation see US patent 4871765) (0.17 g; 0.5 mmol).

The reaction mixture was heated to 85°C for 2 h. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 9: 1 ethyl acetate: hexane as the eluent to give 0.2 g of compound 2 as a white solid. LRMS Hiz = 510 (M+H) +

Title Compound : Compound 2 (0.060 g; 0.12 mmol) was treated with 7 N ammonia in methanol (2 mL) and heated to 85°C for 15 minutes in a sealed tube. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 10: 1 chloroform: methanol as the eluent to give 0.024 g of the title compound as a white solid. LRMS 7n/z = 433 (M+H) + EXAMPLES 845 TO 852 Examples 845 to 852 were prepared using methodology described in Example 844. Example Structure Name M+H 845 n O O'N-[l-(Methanesulfonylimino-523 N phenoxy-methyl)-4-phenyl-piperidin- tNX W 4-ylmethyl]-2-methoxy-benzamide I N flY oxo 846 o O O'N-[l-(Amino-methanesulfonylimino-446 wN A methyl)-4-phenyl-piperidin-4- H ylmethyl]-2-methoxy-benzamide N OF oil'- 847 o (Dr'N- [l- (Cyclopropylamino- 486 w N) 4 methanesulfonylimino-methyl)-4- phenyl-piperidin-4-ylmethyl]-2- methoxy-benzamide H ovSs I zozo 848 n O o'N-{l-[(Cyclopropylmethyl-amino)-500 w NA methanesulfonylimino-methyl]-4- C j H W phenyl-piperidin-4-ylmethyl}-2- methoxy-benzamide N N H oçlSI X 0 Example Structure Name M+H 849 0 0 N- (l- {Methanesulfonylimino- 537 wN J [(pylidin-2-ylmethyl)-amino]- t J H Q methyl}-4-phenyl-piperidin-4- N ylmethyl)-2-methoxy-benzamide N,-'i" °6 H S 850 n o o'N-{l-[Methanesulfonylimino-(2-551 wN% h pyridin-4-yl-ethylamino)-methyl]-4- N N H'phenyl-piperidin-4-ylmethyl}-2- LNXN methoxy-benzamide H S H O 851 o 0-"N- {l- [ (2-Hydroxy-ethyiamino)- 490 N methanesulfonylimino-methyl]-4- t j H 1 phenyl-piperidin-4-ylmethyl}-2- p Y pp Y Y N methoxy-benzamide H 0 OO 852 oo N- {l- [ (3-Imidazol-l-yl- 554 YXNJ propylamino)-methanesulfonylimino- N methyl]-4-phenyl-piperidin-4- NoN/\NXN ylmethyl}-2-methoxy-benzamide H Cl"_ p'- O EXAMPLE 853

Synthesis

Compound 1: Compound 1 was prepared as described in Example 653.

Compound 2: A solution of compound 1 (0.211 mg; 0.68 mmol) in anhydrous acetonitrile (5 mL) was treated with dipenyl N-cyanocarbonimide (0.180 mg; 0.76 mmol) and heated to 85°C for 1 h. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 7: 3 ethyl acetate: hexane as the eluent to give 0.273 g of compound 2 as a white foam. LRMS 7n/z = 457 (M+H) + Title Compound: Compound 2 (0.061 g; 0.13 mmol) was treated with 7 N ammonia in methanol (2 mL) and heated to 60°C for 1 h in a sealed tube. The solvent was removed by rotary evaporation and the crude residue was purified by preparative reverse phase HPLC to give 0.030 g of the title compound as a white solid. LRMS m/z = 379 (M+H) + EXAMPLES 854 TO 915 Examples 854 to 915 were prepared using methodology described in Example 25 and Example 853. Example Structure M+H 854 F 411 zu B-- t ! N I I N 855 F 440 111 t N 1 N NN- III H N Example Structure M+H 856 F 503 O O' lut6 H N NN rN\ I N N 857 F 520 O O' Ho-6 N N N"N"-a II H F N 858 o (a, 478 w N I w Q H ! LJ N HUB O NN% N ru 859 o o'477 N HII-B r'N ,-, nu , NJ 860 X X 499 zon Jl H N"N., H H 861 0 0 11 434 N N " N\N% N H Example Structure M+H 862 JX 408 N HII-B N N H2NoN1N H 863 o o'480 w N w Hz XNX -C 0 H 864 X H X 551 <N H O non H H H H 865 o nue 451 H2N---'N (MHZ zon L N H H 866 F o 0/489 N H N ICI I I N 867 i I F p p 411 N H-l't N NT"NH2 I I N Example Structure M+H 868 i I F p p 440 N I" N N II H N 869 i I F p p 503 N H N ; NHX III H N i N 870 F 503 LIEZ N NON III H/N N N 'N N N O N1% N 0 H 872 o o, 478 N H N N ,..,. N% N J H 873 O'S01 O O' N w H N Np I I I N Example Structure M+H 874 423 O O' N H r NH2 N 875 or*, 452 n o o O O' H-1-6 I N H IN H N 876 or,, 515 o X N H, N N*' H N N 877 or"515 O O' N HIE-6 It. 6 NON H N N 878 i I o O'478 N Hz 0 NN N O Nl% N H 879 0 0 487 N N N Ho N N ' Example Structure M+H 880 a (D'409 N N HO N N 8 81 S 4 5 4 w N I Ho N NU in N H 882 438 O O' N N H N N HO I N-N 883 i I F O O 505 N HO NI v'own ICI N 884 XNß 427 N N HO HO HAN ICI N 885 X HX 512 N N HA N 0 N,"N CH III N Example Structure M+H 886 ci 505 N% Nô N H , Non 887 F F 507 N zon N I N 888 F F 429 O O' N I w H2N N H ion N 889 F W t k F 523 N P M NON N-CN 890 F F 494 I i O NH2 non X of SH NX NON 891 FxF 445 U 0 cl H2N N H H2NtN HH NyN 892 F F 416 0-nu2 Non NgNsmNSH NX X NUS Example Structure M+H 893 458 O N 2 N, i 0 : H N ) ! N 894 C O NH2 408 L 0 NH2 H NtNCH NNJ H NJ Ici N N 895 cri 428 XHt N H-1-6 N NH N NH 896 C O NH2 465 L 0 NHs -0 H NN N H N,,, ; N N N 897 C O NH2 408 O NH2 Non , N N H NS N f N 898 Cl 492 XHRN3X2 Non H NU N O Example Structure M+H 899 F 476 0 NH2 NtNtO H NU N O 900pu555 /O O w : ; HO N ! ! N F o o' ZON LJ o o rKN-\j YOI N 477 NAG 902 Cl 415 ri NH2 NON N N N "NNHs N% N, XNH 903 F 398 X NH2 Non H NJ N N% N, XNH 904o 0507 N I w JE/ N N I N% N'tO Example Structure M+H 905 F 0 NH2 494 F F : N<I X H NJ O-C ! 906 4, F o 0/428 F N J H N N 'N1NH2 907 F 0 NH2 415 ti i H N (J H N N NH2 908,,/N, O NH2 447 F w NN F F C H NJ F NtN1NH2 909 0 nu2 393 /O N 2 H non , N N H NC N N N 910 423 H N I N Dry 9 O tH2 HO ìN N 911 C oXH2 438 H N I N ) i i H rr" so~N ìN/'H NX ly r5 N TUF N Example Structure M+H l. _ _ 1 0 NH2 H NON F-,,,, H N Ion N N 913 0 nu2 471 N H N I H NN N N \H NJ N N N 914 F 428 rT'" N H , N N NH 915 F 415 i F O NH2 tl 1 N H N N N'"NHs EXAMPLE 916

3-Amino-pyrazine-2-carboxylic acid (4-phenyl-l-pyrimidin- 2-yl-piperidin-4-ylmethyl)-amide Synthesis

Compound 1: Compound 1 was prepared using methodology described in Example 653.

Title Compound : The title compound was prepared using methodology described in Example 521 and purified by preparative reverse phase HPLC to give a white solid. LRMS 71iz 390 (M+H) +.

EXAMPLES 917 TO 924 Examples 917 to 924 were prepared using methodology described in Example 916. Example Structure Name M+H 917 F F 3-Amino-pyrazine-2-459 F carboxylic acid [1-pyrimidin- 0 NH2 2-yl-4- (3-trifluoromethyl- phenyl)-piperidin-4-ylmethyll- N H N amide WN 918 3-Amino-pyrazine-2-421 0 NH2 carboxylic acid [1- (4- NN methoxy-pyrimidin-2-yl)-4- OnNonNu H NoS phenyl-piperidin-4-ylmethyl]- amide- 919 3-Amino-pyrazine-2-459 0 NH2 carboxylic acid [4-phenyl-1- (4-trifluoromethyl-pyrimidin- F H No 2-yl)-piperidin-4-ylmethyl]- amide Example Structure Name M+H 920 F 3-Amino-pyrazine-2-409 O NH2 carboxylic acid [4- (3-fluoro- < N) 9N phenyl)-1-pyrimidin-2-yl- H N J piperidin-4-ylmethyl]-amide N 921 F F 3-Amino-pyrazine-2-410 W NH2 carboxylic acid [4- (3, 5- 1\ nNXN difluoro-phenyl)-1-pyrimidin- N<Ns H N 2-ylpiperidin-4-ylmethyl]- amide kan 922 < O NH2 3-Amino-pyrazine-2-427 carboxylic acid [4- (2, 5- NXYI difluoro-phenyl)-l-pyrimidin- N 2-yl-piperidin-4-ylmethyl]- amibe NU- 923 F N- [4- (2, 3-Difluoro-phenyl)-1- 439 XF O Oz pyrimidin-2-yl-piperidin-4- N) L'IB ylmethyl]-2-methoxy- H benzamide I N 924 F 3-Amino-pyrazine-2-426 0 NH2 carboxylic acid [4- (2, 3- vX<N) N difluoro-phenyl)-1-pyrimidin- 0 31 H N 2-yl-piperidin-4-ylmethyl]- amide NU EXAMPLE 925

3-Amino-pyrazine-2-carboxylic acid (4-phenyl-l-pyrimidin- 2-yl-piperidin-4-ylmethyl)-amide Synthesis

Compound 1: Compound 1 was prepared as described in Example 653.

Title Compound : A solution of compound 1 (0.072 g; 0.23 mmol) in anhydrous acetonitrile (2 mL) was treated with polystyrene-diisopropylethylamine (300 mg) and hydrocinnamoyl chloride (0.045 g; 0.27 mmol) at room temperature.

The reaction was shaken for 24 h, filtered and concentrated by rotary evaporation.

The crude residue was purified by preparative reverse phase HPLC to give 0.054 g of the title compound as white solid. LRMS ii7/z = 444 (M+H) + EXAMPLES 926 TO 929 Examples 926 to 929 were prepared using methodology described in Example 925.

Example Structure Name M+H 926 4-1 [ (3-Aniino-pyrazine-2- 385 9 O tH2 carbonyl)-amino]-methyl}-4- N phenyl-piperidine-l-carboxylic ON H N acid ethyl ester 0 o 927 n 3-Amino-pyrazine-2-carboxylic 417 0 NH2 acid (1-benzoyl-4-phenyl- N N piperidin-4-ylmethyl)-amide N H NJ O 928 3-Amino-pyrazine-2-carboxylic 418 0 NH2 acid [4-phenyl-l- (pyridine-3- _, N N carbonyl)-piperidin-4-ylmethyl]- N J H N J amide O 929 3-Amino-pyrazine-2-carboxylic 418 0 NH2 acid [4-phenyl-l- (pyridine-4- N carbonyl)-piperidin-4-ylmethyl]- k XNJ H N, amide 0 EXAMPLE 930 3-Amino-pyrazine-2-carboxylic acid [1- (l-amino-2-nitro-vinyl)- 4-phenyl-piperidin-4-ylmethyl]-amide Synthesis

Compound 1: Compound 1 was prepared as described in Example 653.

Compound 2: A solution of compound 1 (0.065 g; 0.21 mmol) in anhydrous acetonitrile (3 mL) was treated with 1, 1-bis (methylthio) -2-nitroethylene (0.058 g; 0.35 mmol) and heated at 85°C for 3 h. The solvent was removed by rotary evaporation and the crude residue was purified by recyrstallization from ethyl acetate to give 0.068 g of compound 2 as a bright yellow solid. LRMS 771/Z = 430 (M+H) + Title Compound: Compound 2 (0.042 g; 0.098 mmol) was treated with 7 N ammonia in methanol (1 mL) and heated at 85°C for 15 min in a sealed tube. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 9: 1 ethyl acetate: hexane as the eluent to give 0.018 g of the title compound as a white solid. LRMS m/z = 398 (m+H) + EXAMPLE 931 3-Amino-pyrazine-2-carboxylic acid [1- (3, 5-dimethyl-isoxazole-4-sulfonyl) - 4-phenyl-piperidin-4-ylmethyl]-amide Synthesis

Compound 1: Compound 1 was prepared using methodology described in Example 653.

Title Compound : A solution of compound 1 (0.043 mg ; 0.14 mmol) in anhydrous acetonitrile (1 mL) was treated with triethylamine (0.1 mL ; 0.7 mmol) and 3, 5-dimethyl-isoxazole-4-sulfonyl chloride (0.040 mg; 0.2 mmol) and allowed to stir at room temperature for 0.5 h. The solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 1 : 1 ethyl acetate: hexane as the eluent to give 0. 012 g of the title compound as a white solid. LRMS m/z = 472 (m+H) + EXAMPLES 932 TO 936 Examples 932 to 936 were prepared using methodology described in Example 931. Example Structure Name M+H L 932-3-Amino-pyrazine-2-471 0 NH2 carboxylic acid [1- (3-fluoro- NN benzenesulfonyl)-4-phenyl- H N piperidin-4-ylmethyl]-amide 0/R0 933 e 3-Amino-pyrazine-2-471 0 NH2 carboxylic acid [1- (4-fluoro- F,, benzenesulfonyl)-4-phenyl- N H N piperidin-4-ylmethyl]-amide cA) Example Structure Name M+H 934 3-Amino-pyrazine-2-478 0 NH2 carboxylic acid [1- (3-cyano- N benzenesulfonyl)-4-phenyl- X N H NoS piperidin-4-ylmethyl]-amide 0 935 n 3-Amino-pyrazine-2-531 0 NH2 carboxylic acid [1- (2- methanesulfonyl- 'N H N benzenesulfonyl)-4-phenyl- S p Sp piperidin-4-ylmethyl]-amide Oalo\ 936 3-Amino-pyrazine-2-419 0 NH2 carboxylic acid [4-phenyl-1- (propane-2-sulfonyl)- N H N/J piperidin-4-ylmethyl]-amide cr b EXAMPLE 937

1- {4- [ (1 H-Indazol-3-ylamino)-methyl]-4-phenyl-piperidin-1-yl}- 3-phenyl-propan-1-one Synthesis i F CIO O F S F NH2 N Lawesson's N N N H reagent N H J i OAOJA NEt3, CH2CI2 2 PhCH3, 1000C 0-0--, < 3 2 1 i N NH N I/\ i I N-NH N CH2CI2 NCH N H ° I/CHCI2 N 1, 4-dioxane, 100 C Op 4 H 4"

Compound 1: Compound 1 was prepared as described in Example 653.

Compound 2: To compound 1 (0.89 g, 3.06 mmol) and triethylamine (0.95 g, 9.36 mmol) in dichloromethane (5 mL) was added 2-fluorobenzoyl chloride (0.53 g, 3.37 mmol). After 1 h, the reaction mixture was diluted with diethyl ether (20 mL) then washed with 1 N sodium hydroxide, water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and concentrated. Purification by silica gel chromatography using 2: 1 hexanes: ethyl acetate as the eluent gave compound 2 (344 mg, 27%) as a colorless oil. 1H NMR (CDC13, 300 MHz) 81. 43 (9H, s), 1.82-1. 91 (2 H, m), 2.15-2. 20 (2 H, m), 3.18-3. 26 (2 H, m), 3.68-3. 74 (4 H, m), 6.32-6. 36 (1 H, m), 7.03 (1 H, dd, J= 6. 1,12. 0 Hz), 7.20- 7.46 (7 H, m), 8.03 (1 H, td, J= 1. 8,7. 9 Hz). LRMS m/z 357 (M+H) +.

Compound 3: Compound 2 (340 mg, 0.82 mmol) and Lawesson's reagent (433 mg, 1.07 mmol) in toluene (3 mL) was heated at 100°C for 3 h then cooled to room temperature. Water (1 mL), saturated aqueous sodium bicarbonate (3 mL) and ethyl acetate (3 mL) were added. After stirring for 20 min, the reaction mixture was diluted with ethyl acetate then washed with water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and

concentrated. Purification by silica gel chromatography using 3: 1 hexanes: ethyl acetate as the eluent gave compound 3 (255 mg, 72%) as a yellow solid. IH NMR (CDC13,300 MHz) 61. 44 (9 H, s), 1.94-1. 98 (2 H, m), 2.17-2. 25 (2 H, m), 3.27-3. 34 (2 H, m), 3.67-3. 75 (2 H, m), 4.15 (2 H, d, J= 5. 0 Hz), 6.95-7. 01 (1 H, m), 7.15 (1 H, td, J= 1. 0,7. 4 Hz), 7.27-7. 63 (7 H, m), 8.07 (1 H, td, J= 1. 9,8. 0 Hz). LRMS m/z 429 (M+H) +.

Compound 4: Compound 3 (250 mg, 0.58 mmol) and hydrazine (187 mg, 5.80 mmol) in 1,4-dioxane (3 mL) was heated at 100°C for 3 days then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) then washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and concentrated. Purification by silica gel chromatography using 3: 1 hexanes: ethyl acetate as the eluent gave compound 4 (149 mg, 63%) as a white solid. 1H NMR (CDC13, 300 MHz) 81. 43 (9 H, s), 1.90-1. 97 (2 H, m), 2.20-2. 25 (2 H, m), 3.16-3. 25 (2 H, m), 3.64 (2 H, s), 3.64-3. 69 (3 H, m), 6.98 (1 H, td, J= 1. 5,7. 9 Hz), 7.29-7. 35 (5 H, m), 7.42 (4 H, d, J= 4. 4 Hz). LRMS m/z 407 (M+H) +.

Compound 5: Compound 4 (143 mg, 0.35 mmol) in dichloromethane (0.75 mL) and trifluoroacetic acid (0.25 mL) was stirred for 1.5 h then concentrated under reduced pressure. IN Sodium hydroxide (5 mL) was added then extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated to give the compound 5 (107 mg, 100%) as a white solid. LRMS iizlz 307 (M+H) +.

Title Compound: The title compound was prepared using methodology described in Example 390. LRMS nilz 440 (M+H) +.

EXAMPLE 938

4-[(2-Methoxy-benzoylamino)-methyl]-4-phenyl-piperidine- 1-carboxylic acid dimethylamide Synthesis Compound 1: Compound 1 was prepared as described in Example 15.

Compound 2: A solution of compound 1 (0.63 g; 1.9 mmol) in tetrahydrofuran (25 mL) was treated with triethylamine (0.33 mL; 2.4 mmol) and 4- nitro phenyl chloroformate (0.47 g; 2.3 mmol) at room temperature. After 24 h the solvent was removed by rotary evaporation and the crude residue was purified directly by column chromatography on silica gel using 1: 1 ethyl acetate: hexane as the eluent to give 0.53 g of compound 2 as a white foam. LRMS mlz 491 (M+H) +.

Title Compound: Compound 2 (0.050 g; 0.10 mmol) was treated with 2 M dimethylamine in tetrahydrofuran (2 mL) and heated to 65°C in a sealed tube for 12 h.

The solvent was removed by rotary evaporation and the crude residue was purified by

preparative reverse phase HPLC to give 0.018 g of the title compound as a white solid. LRMS ? 396 (M+H) +.

EXAMPLES 939 TO 942 Examples 939 to 942 were prepared using methodology described in Example 938. Example Structure Name |- 939 O O N- [1- (3-Hydroxy-pyrrolidine-1- 440 N carbonyl)-4-phenyl-piperidin-4- CH U ylmethyl]-2-methoxy-benzamide H, N ON OH 940 o 0'2-Methoxy-N-[l-(morpholine-4-440 carbonyl)-4-phenyl-piperidin-4- H ylmethyl]-benzamide H/ N ON Co 941 o O O 2-Methoxy-N- [4-phenyl-1- (pyrrolidine- 424 v X Jw 1-carbonyl)-piperidin-4-ylmethyll- benzamide I N ûAS 942/n O 0'4-[(2-Methoxy-benzoylamino)-methyl]-426 4-phenyl-piperidine-1-carboxylic acid < Mr'1 H isopropyl-methyl-amide I ZON \ EXAMPLE 943

2-Methoxy-N- (4-phenyl-piperidin-4-ylmethyl)-thiobenzamide Synthesis n o o. n f f r) f Lawesson's N N HM Lawesson's HX CF3CO2H XHX H N 10% pyridine CH2CI2 H QJk 1 toluene 0 2 3 Compound 1: Compound 1 was prepared using methodology described in Example 653.

Compound 2: A solution of compound 1 (0.32 g; 0.76 mmol) and Lawesson's reagent (0.38 g; 0.95 mmol) in 10% pyridine in toluene (5 mL) was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL), water (2 mL) and saturated aqueous sodium bicarbonate (5 mL) and stirred for 0.5 h. Additional ethyl acetate was added and the organic layer was separated, washed with water and saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated. The crude residue was purified by column chromatography on silica gel using 3: 1 hexane: ethyl acetate as the eluent to give 0.24 g of compound 2 as a yellow solid. LRMS niez 442 (M+H) +.

Title Compound: Compound 2 (0.044 g; 0.10 mmol) was treated with 0.75 mL dichloromethane and 0.25 mL trifluoroacetic acid and the reaction mixture was stirred at room temperature for 0.5 h. The solvents were removed by rotary evaporation to give 0.040 g of the title compound as the trifluoroacetic acid salt as a white solid that was used without additional purification. LRMS m/z 341 (M+H) +.

EXAMPLES 944 TO 947 Examples 944 to 947 were prepared using methodologies described in Example 943 and Example 15, Example 16 or Example 25.

Example Structure Name M+H 944 s o'N- (I-Dimethylsulfamoyl-4-phenyl- 450 w I N I piperidin-4-ylmethyl)-2-methoxy- C 9 H W thiobenzamide OvO IN O f i 945 s S 0'2-Methoxy-N-(4-phenyl-1-sulfamoyl-422 AJ, X9N piperidin-4-ylmethyl)-thiobenzamide H ION O=S=O NH2 946 i I S O'487 N H k 0 NfO'v N H N N NN''NH2 EXAMPLE 948 N- [l- (N-Ethylcarbamimidoyl)-4-phenyl-piperidin-4-ylmethyl]-2-meth oxy-benzamide Synthesis

Compound 1: Compound 1 was prepared using methodology described in Example 15.

Compound 2: Compound 2 was prepared as described in J. Org. Cheni.

2002,67, 7553-7556.

Compound 3: A solution of compound 1 (0.63 g; 1.9 mmol) and compound 2 (0.45 g; 2.8 mmol) in tetrahydrofuran (15 mL) was heated at 50°C for 24 h. The solvent was removed by rotary evaporation and the residue was treated with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with water and saturated aqueous sodium chloride. The organic layer was separated, dried (sodium sulfate), filtered and concentrated to give 0.7 g of compound 3 as a light yellow foam that was used without additional purification. LRMS iizlz 419 (M+H) +.

Title Compound: Compound 3 (0.059 g; 0.14 mmol) was treated with 2 M ethylamin in tetrahydrofuran (2.5 mL) and heated to 60°C in a sealed tube for 48 h.

The solvent was removed by rotary evaporation and the crude residue was purified by preparative reverse phase HPLC to give 0.022 mg of the title compound as the trifluoroacetic acid salt as a white solid. LRMS m/z 396 (M+H) +.

EXAMPLE 949

3-Amino-pyrazine-2-carboxylic acid (4-p-tolyl-tetrahydro-pyran-4-ylmethyl)-amide Synthesis Compound 1: Compound 1 is commercially available.

Compound 2: A solution of compound 1 (0.71 g; 5 mmol), 4-methyl benzyl cyanide (0.66 g; 5 mmol) and hexadecyl tributyl phosphonium bromide (0.13 g; 0. 25 mmol) in 50% NaOH in water (8 mL) was heated at 100°C for 2 h. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with diethyl ether (3 x 10 mL). The combined organic layers were washed with water and saturated aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated.

The crude residue was purified by column chromatography on silica gel using 8.5 : 1.5 hexane: ethyl acetate as the eluent to give 0.776 g of compound 2 as a yellow oil.

LRMS walz 202 (M+H) +.

Compound 3: Compound 3 was prepared using methodology described in Example 15. LRMS mlz 206 (M+H) +.

Title Compound: The title compound was prepared using methodology described in Example 653. LRMS m/z 327 (M+H) +.

EXAMPLES 950 TO 955 Examples 950 to 955 were prepared using methodology described in Example 949. Example Structure Name M+H 950 n O NH2 3-Amino-pyrazine-2-carboxylic 313 i/+NXN acid (4-phenyl-tetrahydro-pyran-4- i-ri ylmethyl)-amide o 951 Cl, e O NH2 3-Amino-pyrazine-2-carboxylic 348 2 N N acid [4- (4-chloro-phenyl)- C X H NX tetrahydro-pyran-4-ylmethyl]- H NJ amide 952 n O NH2 3-Amino-pyrazine-2-carboxylic 331 F N-T lN acid [4- (3-fluoro-phenyl)- H N tetrahydro-pyran-4-ylmethyl]- 0 amide 953 1-0 0 NH 3-Amino-pyrazine-2-carboxylic 343 acid [4- (4-methoxy-phenyl)- C X H NS tetrahydro-pyran-4-ylmethyl]- H NJ amide 954 0 NH2 3-Amino-pyrazine-2-carboxylic 349 acid [4- (2, 4-difluoro-phenyl)- tetrahydro-pyran-4-ylmethyl]- amide 0 955 F i O NH2 3-Amino-pyrazine-2-carboxylic 331 acid [4- (4-fluoro-phenyl)- C X H NS tetrahydro-pyran-4-ylmethyl]- H NJ amide EXAMPLE 956

2-Methoxy-N- (4-phenyl-azepan-4-ylmethyl)-benzamide Synthesis / con CN NaN3/AcOHNbenzoic anhydrideN1) LAH, THF / H pyridine, toluene02) o-anisic acid CDC, DCM 0 1 2 3 /O O 1) 1-Chloroethylchloroformate, dé, TEA N . H I _ H I/ N 2) MESH 0' Compound 1: Compound 1 is commercially available Compound 2: To a solution of ketone 1 (500mg, 2.51 mmol) in glacial acetic acid (30mL) was added concentrated sulfuric acid (0.3mL) at room temperature. The solution was heated to 65°C and sodium azide (0.50g, 7. 7mmol) was added in 3 equal portions over 5 min at 65°C. After a further 5 min at 65°C, the reaction mixture was allowed to cool and stirred at ambient temperature for 16 h. The resulting slurry was poured cautiously into a saturated NaHC03 solution (ca. lOOmL), transferred to a separation funnel and the aqueous portion extracted with dichloromethane (3 x 50mL). The combined organic portions were washed with NaHC03 (20mL), dried over Na2S04, decanted and concentrated yielding a pale yellow oil. Methanol (ca.

5mL) was added to the oil and the white precipitate was collected and dried under

high vacuum (153mg). The methanol solution was purified by preparative HPLC.

YMC ODS S5 30 x 50mm, 10 min gradient, 0-100% MeOH (90% in water, 0. 1% TFA) UV detection 220nM, 50mL/min flow rate. The product retention time was 5.23 min. The product was neutralized with saturated NaHC03 and extracted into dichloromethane. A further 119 mg of product was isolated and combined with the product isolated by precipitation, (combined mass 272mg, yield 51%). HPLC Rt 2. 17min, Purity 98%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0. 1% PPA) UV detection at 220nm. LCMS Rt 1. 12min, [M+1] 215.42 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220nm. NMR H (DMSO) 1.98ppm, 1H, multiplet; 2. 10ppm, 1H, multiplet; 2.30ppm, 1H, multiplet; 2.78ppm, 1H, multiplet ; 3.21ppm, 1H, multiplet; 3.43ppm, 1H, multiplet; 7.31ppm, 1H, t, J=7.9Hz ; 7.42ppm, 2H, dd, J=7.9Hz and J=7.9Hz ; 7.55ppm, 2H, d, J=8.4Hz ; 7.82ppm, 1H, s.

Compound 3: Benzoic anhydride (4.22 g, 18.7 mmol) and pyridine (3.1 mL, 37 mmol) were added to a suspension of compound 2 (2.00 g, 9.33 mmol) in toluene (20 mL). After heating at 100°C for 18 hours, the reaction mixture was concentrated and purified by ISCO hexane/EtOAc, 0% EtOAc-10% EtOAc over 10 minutes, 10% EtOAc-30% EtOAc over 10 minutes, 30% EtOAc for 20 minutes, 30% EtOAc- 100% EtOAc over 2 minutes, 100% EtOAc for 5 minutes. Compound 3 eluted at a retention time of 12. 8min as a white solid (2.62 g, 88% yield). HPLC Rt 3. 08min, Purity 86%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0.1% PPA) UV detection at 220nm. LCMS Rt 1. 57min, [M+1] 319.18 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220nm. NMR H (CDC13) 2.23ppm, 2H, multiplet; 2.37ppm, 1H, multiplet ; 2.47ppm, 1H, multiplet; 2.76ppm, 1H, multiplet; 3.34ppm, 1H, multiplet; 3.91ppm, 1H, dd, J=12.0 and 16. OHz ; 4.66ppm, 1H, dd, J=12.0 and 16. OHz ; 7.44ppm, 8H, multiplet; 7.57ppm, 2H, multiplet.

Compound 4: To a solution of compound 3 (500 mg, 1.57 mmol) in CH2C12 (8 mL) and THF (4 mL) was added a 1.0 M solution of lithium aluminum hydride in THF (9.4 mL, 9.4 mmol) at 0°C. The reaction mixture was allowed to warm up to

room temperature and stirred for 18 hours. The reaction was quenched with H20 (1.7 mL), 1 N NaOH (1.0 mL) and H20 (1.7 mL). After stirring at room temperature for 30 minutes, the reaction was filtered and the filtrate was concentrated. The resulting residue was dissolved in CH2C12 (75 mL). The organic layer was washed with brine (25 mL), dried over MgS04, filtered, concentrated, and the resulting residue was dissolved in CH2C12 (2.0 mL). The solution was added to a solution of O-anisic acid (215 mg, 1.42 mmol) and EDCI (296 mg, 1.54 mmol) in CH2C12 (2 mL). After 2 hours, the reaction mixture was concentrated and purified by ISCO Hexane/EtOAc; 0% EtOAc-30% EtOAc over 10 minutes, 30% EtOAc-50% EtOAc over 10 minutes, 50% EtOAc for 10 minutes, 50% EtOAc-100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes. Compound N+2 eluted at a retention time of 13. 3min as a white solid compound (211 mg, 31%). HPLC Rt 2. 40min, Purity 100%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0. 1% PPA) UV detection at 220nm. LCMS Rt 1. 46min, [M+1] 429.22 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220nm. NMR H (CDC13) 1.63ppm, 1H, multiplet ; 1.75ppm, 1H, multiplet; 1.89ppm, 1H, multiplet; 1.99ppm, 1H, multiplet; 2.22ppm, 2H, multiplet; 2.61ppm, 4H, multiplet; 2.92ppm, 3H, s; 3.54ppm, 2H, s; 3.64ppm, 2H, d, J=4. OHz ; 6.75ppm, 1H, d, J=8. OHz ; 6.96ppm, 1H, t, J=6.0 Hz; 7.20ppm, 6H, multiplet; 7.30ppm, 5H, multiplet; 7.50ppm, 1H, multiplet; 8. 11ppm, 1H, dd, J=4.0 and 8. 0Hz.

Title Compound: At 0°C 1-chloroethyl chloroformate (159 pL, 1.48 mmol) was added to a solution of compound 4 (211 mg, 0.492 mmol) and TEA (341 rL, 2.45 mmol) in dichloroethane (5 mL). The reaction was allowed to warm up to room temperature and stirred for 3 hours. The reaction mixture was concentrated and dried on oil pump for 0.5 hours. The solution of the resulting residue in MeOH (5 mL) was heated under reflux for 5 hours and concentrated. Crude product was purified by preparative HPLC YMC ODS S5 30 x 100 mm Ballistic column 10-100% MeOH (90% in water, 0. 1% TFA) gradient over lOmin with flow rate 40mL/min and UV detection at 220nm. Compound 5 eluted at a retention time of 6.6mins and was isolated as a yellow oil (101.3mg, yield 61%) NMR H (CDC13) 1.60ppm, 1H,

multiplet; 1.91ppm, 3H, multiplet ; 2.34ppm, 2H, multiplet ; 3.22ppm, 2H, multiplet; 3.36ppm, 1H, multiplet; 3.52ppm, 1H, multiplet; 3.53ppm, 3H, s; 3.62ppm, 2H, multiplet; 6.76ppm, 1H, d, J=1. 8Hz ; 6.80ppm, 1H, d, J=7.9Hz ; 6.98ppm, 1H, t, J=7.7 Hz; 7.06ppm, 1H, d, J=1. 8Hz ; 7.22ppm, 1H, multiplet; 7.34ppm, 3H, multiplet; 7.56ppm, 1H, t, J=5.7Hz ; 8. 1 lppm, 1H, dd, J=1.8 and 7.5Hz.

EXAMPLE 957 N-(1-Benzyl-4-phenyl-azepan-4-ylmethyl)-2-methoxy-benzamide Synthesis: 9 1 0 I, 0 I w I _N N benzyl bromide N 1) LAH, THF N SNH NaH, DMF S 2) o-anisic acid d EDCI, DMF 1 2 3 1 2 3 Compound 1: Compound 1 was synthesized as described in Example 956.

Compound 2: NaH (95%) (71 mg, 2.8 mmol) was added to the suspension of compound 1 (500 mg, 2.33 mmol) in DMF (10 mL). After 30 minutes benzylbromide (333 uL, 2.80 mmol) was added and the reaction was stirred for 18 hours. LiCl (10%, 50 mL) was added. The aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over MgS04, filtered, concentrated and purified by ISCO Hexane/EtOAc, 0% EtOAc to 10% EtOAc over 10 minutes, 10% EtOAc for

5 minutes, 10% EtOAc to 30% EtOAc over 10 minutes, 30% EtOAc for 10 minutes, 30% EtOAc to 100% EtOAc over 5 minutes. Compound N + 1'eluted at 23min as a clear oil (454.7 mg, 64% yield).

Title Compound: At room temperature a 1.0 M solution of Lithium aluminum hydride in THF (480 pL, 0.480 mmol) was added to a solution of compound 2 (48.5 mg, 0.160 mmol) in THF (1 mL). After 3 hours the reaction mixture was quenched with H20 (60 tel), 1 N NaOH (36 ßL) and H20 (60 pL). The reaction was stirred at room temperature for 0.5 hours, dried over MgS04, filtered and concentrated. The solution of the resulting residue in CH2C12 (1 mL) was added to the mixture of o-anisic acid (27 mg, 0.18 mmol) and EDCI (37 mg, 0.19 mmol) in CH2C12 (1 mL). After 1 hours the reaction was concentrated and purified by preparative HPLC yielding compound N+2 as a yellow oil (17.5 mg, 26%).

EXAMPLE 958 2-Methoxy-N-(4-phenyl-1-sulfamoyl-azepan-4-ylmethyl)-benzami de Synthesis

Compound 1: Compound 1 was synthesized as described in Example 956.

Compound 2: At 0°C N, N'-sulfuryl bis-2-methylimidazole mono-methyl triflate salt (317 mg, 0.390 mmol) was added to a solution of compound 1 (101 mg, 0.300 mmol) in acetonitrile (10 mL) followed by the addition of TEA (100 fol). The reaction was allowed to warm up to room temperature and stirred for 18 hours. The mixture was concentrated and purified by ISCO hexane (0. 1% TEA) /EtOAc, 0% EtOAc-50% EtOAc over 15 minutes, 50% EtOAc for 15 minutes, 50% EtOAc- 100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes. Compound 2 eluted at a retention time of 26min as a yellow oil (78.8 mg, 54% yield) NMR H (CDC13) 1.58ppm, 1H, multiplet; 1.89ppm, 3H, multiplet; 2.35ppm, 2H, multiplet; 2.45ppm, 3H, s; 3.20ppm, 2H, multiplet; 3.37ppm, 1H, multiplet; 3.51ppm, 1H, multiplet; 3.53ppm, 3H, s; 3.62ppm, 2H, multiplet; 6.76ppm, 1H, d, J=1. 8Hz ; 6.80ppm, 2H, multiplet; 6.98ppm, 1H, t, J=7.5 Hz; 7.06ppm, 1H, d, J=1. 8Hz ; 7.23ppm, 2H, multiplet; 7.33ppm, 3H, multiplet; 7.56ppm, 1H, t, J=5.7Hz ; 8. 10ppm, 1H, dd, J=1. 8 and 7. 9Hz Title Compound: A solution of compound 2 (34 mg, 0.070 mmol) in CH2C12 (1 mL) was added methyl trifluoromethanesulfonate (8 sIL, 0.08 mmol) at 0°C. After

1.5 hours, the reaction was concentrated to give crude product of compound 3 as a white foam. This product was used directly to the next step without further purification. A 2.0 M solution of NH3 in MeOH (170 ßL, 0.35 mmol) was added to a solution of compound 4 and TEA (100 gL) in acetonitrile (1 mL). The reaction mixture was heated at 80°C for 8 hours. The concentrated reaction mixture was purified by preparative HPLC YMC ODS S5 30 x 100 mm Ballistic column 10-100% MeOH (90% in water, 0. 1% TFA) gradient over 12min with flow rate 40mL/min and UV detection at 220nm. Compound 5 eluted at a retention time of 9. 6mins and was isolated as a clear oil (18.27 mg, 63% yield from compound 3). HPLC Rt 2. 91min, Purity 100%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0. 1% PPA) UV detection at 220nm. LCMS Rt 1. 60min, [M+1] 418.17 YMC-ODS S5 column 4.6 x 33 mm, 2min gradient 0 to 100% MeOH (90% in water, 10 mM NH40Ac) UV detection at 220nm. NMR H (CDC13) 1.65ppm, 1H, multiplet; 1.84ppm, 2H, multiplet; 1. 99ppm, 2H, multiplet ; 2.25ppm, 1H, multiplet ; 2.37ppm, 2H, multiplet ; 3.23ppm, 2H, multiplet; 3.31ppm, 1H, multiplet ; 3.52ppm, 3H, s; 3.57ppm, 2H, s; 3.69ppm, 1H, multiplet; 4.40ppm, 2H, bs; 6.79ppm, 1H, d, J=8.4Hz ; 6.97ppm, 1H, t, J=7.5Hz ; 7.23ppm, 1H, multiplet; 7.34ppm, 5H, multiplet; 7.61ppm, 1H, multiplet; 8.09ppm, 1H, dd, J=1.7 and 7.9Hz.

EXAMPLES 959 TO 963 Compounds 959 to 963 were synthesized using methodology described in Example 958. Example Structure Name [M+1] 959 0 oll 2-Methoxy-N- [I- (2-methoxy- 476 nSNJX ethylsulfamoyl)-4-phenyl-azepan-4- tNmp ~°-ylmethyl]-benzamide '-N ó, ~N 0 N- [l- (2-Hydroxy-ethylsulfamoyl)-4-phenyl- 462 TSNX azepan-4-ylmethyl]-2-methoxy-benzamide 618-N - o S-N Example Structure Name [M+1] 961 0 oll 2-Methoxy-N-1 1- [ (2-methoxy-ethyl)- 490 wnaNJX methyl-sulfamoyl]-4-phenyl-azepan-4- -benzamide N" ó, Nx 962 C JA N-(l-Cyclopropylsulfamoyl-4-phenyl-458 C) W azepan-4-ylmethyl)-2-methoxy-benzamide N, o NIP zu 963 o o'2-Methoxy-N- (l-methylsulfamoyl-4-phenyl- 432 N azepan-4-ylmethyl)-benzamide NIP" ó, S N EXAMPLE 964

N- (l-Dimethylsulfamoyl-4-phenyl-azepan-4-ylmethyl)-2-methoxy-b enzamide Synthesis

Compound 1: Compound 1 was synthesized as described in Example 956.

Title Compound: Dimethylsulfomoyl chloride (3.44 mg, 0.0240 mmol) was added to a solution of compound 1 (6.76 mg, 0.0200 mmol) in CH2C12 (0.5 mL).

TEA (5) iL) was added and the reaction was stirred at room temperature for 2 hours.

The concentrated reaction mixture was purified by preparative HPLC YMC ODS S5 30 x 100 mm Ballistic column 20-100% MeOH (90% in water, 0.1% TFA) gradient over lOmin with flow rate 40mL/min and UV detection at 220nm. Compound 2 eluted at a retention time of 9. 0min and was isolated as a clear oil (5.7 mg, 64% yield). HPLC Rt 3.30min, Purity 100%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0. 1% PPA) UV detection at 220nm.

LCMS Rt 1. 68min, [M+1] 446.21 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 10 mM NH40Ac) UV detection at 220nm.

NMR H (CDC13) 1.61ppm, 1H, multiplet; 1.89ppm, 3H, multiplet; 2.34ppm, 2H, multiplet; 2.61ppm, 6H, s; 3.18ppm, 2H, multiplet; 3.26ppm, 1H, multiplet; 3.54ppm, 3H, s; 3.57ppm, 3H, multiplet; 6.80ppm, 1H, d, J=8. OHz ; 6.98ppm, 1H, t, J=8. OHz ; 7.23ppm, 1H, multiplet; 7.33ppm, 5H, multiplet; 7.58ppm, 1H, multiplet; 8. l lppm, 1H, multiplet.

EXAMPLE 965 4-Aminomethyl-4- (3-fluoro-phenyl)-azepane-l-carboxylic acid tert-butyl ester Synthesis F F F /I/I I N Boc20, DMAP N 1) superhydride \ N THF 2) Et3SiH, BF3Et2O N nu NH % Boc u Boo 1 2 3 F F Col2, NaBH4 tNH2 MeOH CNH2 N Boc 4

Compound 1: Compound 1 was synthesized via the intermediate cyclohexanone according to the procedures described in Journal of Medicinal Chemistry, 1998, 821. The intermediate cyclohexanone was converted to the lactam as described for Example 956.

Compound 2: To a suspension of the crude compound 1 in THF (20 mL) was added subsequently di-tert-butyl dicarbonate (2.33 mL, 10.1 mmol) and dimethylaminopyridine (1.24 g, 10.1 mmol). After 3 hours the reaction mixture was concentrated. The resulting residue was dissolved in Ethyl acetate (100 mL). The organic layer was washed with 1 N HC1 (2 x 50mL) and dried over MgS04.

Evaporation and purification by ISCO (hexane/EtOAc, 0% EtOAc-10% EtOAc over 10 minutes, 10% EtOAc-30% EtOAc over 10 minutes, 30% EtOAc for 15 minutes, 30% EtOAc-100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes) yielded compound 2 with a retention time of 16min as a white solid (2.69 g, 88% from ketone) NMR H (CDC13) 2.03ppm, 1H, multiplet; 2.28ppm, 3H, multiplet; 2.76ppm, 1H, dd, J=7.2 and 15.6 Hz; 3.21ppm, 1H, multiplet; 3.75ppm, 1H, dd, J=10.5 and 16.3Hz ; 4.44ppm, 1H, dd, J=6.5 and 15. 9Hz; 7.05ppm, 1H, multiplet; 7.16ppm, 1H, multiplet; 7.26ppm, 1H, multiplet; 7.38ppm, 1H, multiplet.

Compound 3: At-78°C a 1.0 M solution of lithium triethylborohydride in THF (4.87 mL, 4.87 mmol) was added to a solution of compound 2 (1.35 g, 4.06 mmol) in THF (25 mL). After 30 minutes the reaction was quenched with saturated NaHC03 (7.6 mL) and warmed to 0°C. At 0°C H202 (12 drops) was added and the reaction was stirred for 20 minutes. THF was removed and the aqueous layer was extracted with CH2C12 (3 x 25 mL). The combined organic layers were dried over MgS04, filtered and concentrated. The resulting thick oil was dissolved in CHzClz (50 mL). At-78°C triethylsilane (648 jiL, 4.06 mmol) was added followed by drop wise addition of boron trifluoride etherate (566 FL, 4.47 mmol). After 30 minutes another portion of triethylsilane (648 gL, 4.06 mmol) and boron trifluoride etherate (566 rL, 4.47 mmol) were added and the reaction was continued to stir for 2 hours at - 78°C. The reaction was quenched with saturated NaHC03 (15 mL). The aqueous layer was extracted with CH2C12 (3 x 20 mL) and the combined organic layers were dried over MgS04, filtered and concentrated to give crude compound 3 (1.19 g) as an oil. This crude product was used to the next step directly without further purification.

Title Compound: To a solution of crude compound 3 (1.19 g, 3.73 mmol) in MeOH (35 mL) was added cobalt (II) chloride hexahydrate (1.41 g, 7.46 mmol). The resulted purple mixture was stirred at room temperature for 10 minutes. At 0°C NaBH4 (1.41 g, 37.3 mmol) was added in three portions over 25 minutes. The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a black residue. The black residue was dissolved in 30% ammonium hydroxide solution (100 mL), extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated to give a crude pink solid of compound 4 (1.46 g). This crude solid was used directly to the following acylation reaction.

EXAMPLE 966

N- [4- (3-Fluoro-phenyl)-azepan-4-ylmethyl]-2-methoxy-benzamide Synthesis Compound 1: The synthesis of Compound 1 is described for Example 965.

Compound 2: To a solution of crude compound 1 (729 mg, 2.26 mmol), o- anisic acid (345 mg, 2.26 mmol) and TEA (314 rL, 2.26 mmol) in CH2C12 (10 mL) was added PyBrOP (1.05 g, 2.26 mmo) at room temperature. After 3 hours, the reaction was concentrated and purified by flash chromatography using Hexane/EtOAc (2/1) to yield compound 2 as a white solid (536.2 mg, 58% from compound N+13).

HPLC Rt 3.79min, Purity 100%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0. 1% PPA) UV detection at 220nm.

LCMS Rt 2.04min, [M+1] 357.43 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 0. 1% TFA) UV detection at 220nm. NMR H (CDC13) 1.38ppm, 9H, d, J=12.8Hz ; 1.64ppm, 1H, multiplet; 1.78ppm, 3H, multiplet ; 2.32ppm, 2H, multiplet; 3. 31ppm, 3H, multiplet ; 3.65ppm, 6H, multiplet;

6.89ppm, 1H, d, J=8.4Hz ; 6.99ppm, 1H, multiplet; 7.06ppm, 2H, multiplet; 7.16ppm, 1H, d, J=7.5Hz ; 7.40ppm, 2H, multiplet; 7.62ppm, 1H, multiplet; 8.20ppm, 1H, d, J=7.5Hz.

Title Compound: To a solution of compound 2 (526 mg, 1.24 mmol) in CH2C12 (5 mL) was added a solution of TFA (1 mL) in CH2C12 (4 mL) at room temperature. After 1.5 hours the reaction was diluted with CH2C12 (50 mL) and was washed with saturated NaHCO3 (2 x 20 mL), dried over MgS04, filtered and concentrated to give a crude product of compound N+18 as a white solid (483 mg, quantitative yield). The crude product was used directly to the next step without further purification.

EXAMPLES 967 TO 970 Compounds 967 to 970 were prepared using the methodology described for Example 966 and Example 958. Example Structure Name [M+1] |--ll 967 F 0 cr, N- [4- (3-Fluoro-phenyl)-I- (2-methyl- 501 N imidazole-l-sulfonyl)-azepan-4-ylmethyl]-2- ><irS -/ methoxy-benzamide N o=,, N4N 0 968 F o N- [1-Cyclopropylsulfamoyl-4- (3-fluoro- 476 N phenyl)-azepan-4-ylmethyl]-2-methoxy- N benzamide N O-N ° b 969 F o o'N-{4-(3-Fluoro-phenyl)-1-[(2-methoxy-508 I ethyl)-methyl-sulfamoyl]-azepan-4- ylmethyl}-2-methoxy-benzamide N - O \ 970 F N- [4- (3-Fluoro-phenyl)-l-sulfamoyl-azepan- 436 tNJt 4-ylmethyl]-2-methoxy-benzamide o, N_N o EXAMPLE 971

Synthesis Compound 1: The synthesis of Compound 1 is described for Example 965.

Compound 2: To a solution of crude compound 1 (729 mg, 2.26 mmol) and 3-aminopyrazine-2-carboxylic acid (377 mg, 2.26 mmol) in ethylene glycol dimethyl ether (10 mL) was added drop wise diethyl phosphoryl cyanide (411 µL, 2.71 mmol) and TEA (630 p, L,, 4.52 mmol) respectively at 0°C. The reaction was stirred at 0°C for 1 hour and at 40°C for 1 hour under N2. The mixture was diluted with EtOAc (100 mL) and washed with H20 (25 mL), saturated NaHC03 (25 mL) and H20 (25 mL) successively. The organic layer was dried over MgS04 and concentrated to afford the crude product, which was purified by ISCO Hexane/EtOAc; 0% EtOAc-50% EtOAc over 10 minutes, 50% EtOAc for 25 minutes, 50% EtOAc-100% EtOAc over 5 minutes, 100% EtOAc for 5 minutes. Compound 2 eluted at a retention time of 14min as a yellow solid (432.7 mg, 51% from compound 1). HPLC Rt 3. 67min, Purity 100%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100%

MeOH (90% in water, 0. 1% PPA) UV detection at 220nm. LCMS Rt 1. 90min, [M+1] 344.45 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220nm. NMR H (CDC13) 1.38ppm, 9H, d, J=12.8Hz ; 1.62ppm, 1H, multiplet ; 1.71ppm, 1H, mutiplet; 1.87ppm, 2H, multiplet; 2.34ppm, 2H, multiplet; 3.17ppm, 2H, multiplet; 3.38ppm, 1H, multiplet; 3.46ppm, 2H, multiplet; 3.67ppm, 1H, multiplet; 6.99ppm, 2H, multiplet; 7. 11ppm, 1H, multiplet ; 7. 37ppm, 1H, multiplet ; 7. 71ppm, 2H, multiplet; 8. 11ppm, 1H, s.

Title Compound: To a solution of compound 2 (457 mg, 1.03 mmol) in CH2C12 (5 mL) was added a solution of TFA (1 mL) in CH2C12 (4 mL) at room temperature. After 1.5 hours the reaction was diluted with CH2C12 (50 mL) and was washed with saturated NaHC03 (2 x 20 mL), dried over MgS04, filtered and concentrated to give a crude product of compound 3 as a yellow solid (291mg, 82% crude yield). The crude product was used directly to the next step without further purification.

EXAMPLES 972 TO 974 Compounds 972 to 974 were prepared using the methodology described for Example 971 and Example 961. Example Structure Name [M+l] 972 F N- [l-Dimethylsulfamoyl-4- (3-fluoro- 464 X < phenyl)-azepan-4-ylmethyl]-2-methoxy- t) W benzamide N I/ 973 F 3-Amino-pyrazine-2-carboxylic acid [1-451 0 N dimethylsulfamoyl-4- (3-fluoro-phenyl)- zu C) NsS azepan-4-ylmethyl]-amide N/ N \ 974 F 3-Amino-pyrazine-2-carboxylic acid [4- (3- 488 a N fluoro-phenyl)-1-(2-methyl-imidazole-1- (D NsS sulfonyl)-azepan-4-ylmethyl]-amide o=, N_NXN o EXAMPLE 975

Compound 1: Compound 1 was prepared as described in Example 671.

Compound 3: N- (tert-Butoxycarbonyl)-N- [4- (dimethylazaniumylidene)-1, 4- dihydropyridin-l-ylsulfonyl] azanide was made according to Organic Letters, 2001, Vol. 3., No. 14,2241-2243. Compound 1 (19 mg, 0.058 mmol) was added to Compound 2 (20 mg, 0.064 mmol) in CH2C12 (1 mL) and was stirred at room temperature for 18 hours. The residue was concentrated and purified by preparative silica thin layer chromatography (25x25cm plate, lmm thickness silica with UV indicator) using Hexane/EtOAc (1/2) as eluent to yield compound 3 as a clear oil (26 mg, 87% yield) NMR H (CDC13) 1.44ppm, 9H, s; 1.64ppm, 1H, multiplet; 1.98ppm, 3H, multiplet; 2.37ppm, 2H, multiplet; 3.24ppm, 2H, multiplet; 3.49ppm, 3H, multiplet; 3. 81ppm, 1H, multiplet; 6.99ppm, 2H, multiplet; 7.35ppm, 1H, multiplet; 7.67ppm, 1H, multiplet; 7.69ppm, 1H, d, J=4. OHz ; 8. 00ppm, 1H, s; 8.12ppm, 1H, d, J=4. 0Hz.

Title Compound: At room temperature, a solution of TFA (0.25 mL) in CH2C12 (1 mL) was added to a solution of compound 3 (26 mg, 0.050 mmol). After 2 hours the reaction mixture was concentrated and purified by preparative HPLC YMC ODS S5 30 x 100 mm Ballistic column 20-100% MeOH (90% in water, 0. 1% TFA) gradient over lOmin with flow rate 40mL/min and UV detection at 220nm.

Compound 4 eluted at a retention time of 7. 0min and was isolated as a clear oil (20.2

mg, 95% yield). HPLC Rt 2. 68min, Purity 100%, Phenomenex Luna S5 column 4.6 x 50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0. 1% PPA) UV detection at 220nm. LCMS Rt 1. 39min, [M+1] 423.31 Phenomenex S5 column 4.6 x 30 mm, 2min gradient 0 to 100% MeOH (90% in water, 10 mM NH4OAc) UV detection at 220nm. NMR H (CDC13) 1.66ppm, 1H, multiplet; 1. 90ppm, 2H, multiplet ; 2. 00ppm, 1H, multiplet; 2.30ppm, 1H, multiplet; 2.41ppm, 1H, multiplet; 3.16ppm, 2H, multiplet; 3.41ppm, 1H, multiplet; 3.51ppm, 2H, multiplet; 3.66ppm, 1H, multiplet; 7. 00ppm, 2H, multiplet; 7. 10ppm, 1H, d, J=8. OHz ; 7.38ppm, 1H, multiplet; 7.60ppm, t, J=6. OHz ; 7.81ppm, 1H, d, J=4. OHz ; 7.93ppm, 1H, multiplet.